CH666892A5 - PHARMACOLOGICALLY ACTIVE COMPOUNDS THAT CAN BE USED TO PREVENT AND TREAT STOMACH. - Google Patents

Description

DESCRIPTION 20 It is the object of the present invention to create new compounds and their therapeutically acceptable salts which inhibit exogenously or endogenously stimulated gastric acid secretion and develop a cell protective action in the gastrointestinal tract and can thus be used for the prevention and treatment of gastric ulcers .

The present invention relates to compounds according to claim 1 and to uses of the compounds according to the invention or their therapeutically acceptable salts for the preparation of agents for inhibiting gastric acid secretion and for the production of cell protection agents for the gastrointestinal tract in humans and mammals . In a more general sense, the compounds of the invention can be used to prevent and treat inflammatory diseases of the gastrointestinal tract in 35 people and mammals, including, for example, gastritis, gastric ulcers and duodenal ulcers. In addition, the compounds can be used to prevent and treat other gastrointestinal disorders where cell protection 40 and / or gastric acid inhibition is desired, e.g. in patients with gastric disorders, in patients with acute upper gastric bleeding and in patients whose medical history indicates chronic alcohol abuse. The invention also relates to pharmaceutical 45 'and veterinary preparations which contain at least one compound according to the invention or a therapeutically acceptable salt thereof as an active component. Furthermore, the invention relates to methods for producing such new compounds according to claim 1 and to novel intermediates for producing the compounds according to the invention according to method claim 11.

Benzimidazole derivatives intended as inhibitors of gastric acid secretion are described in British Patent 55, 1,500,043 and 1,525,958, US Pat. No. 4,182,766, European Patent 0 005 129 and Belgian Patent 890,024. Proposed benzimidazole derivatives for use in the treatment or prevention of certain inflammatory diseases of the gastrointestinal tract are described in European patent application publication number 0 045 200.

The compounds of Formula I below and their physiologically acceptable salts have been found to be effective as cell protective agents for the gastrointestinal tract and as agents for inhibiting gastric acid secretion in humans and mammals. These compounds correspond to formula I.

666 892

6

X CH

(I

R

R

where X is -S- or t

-S- /

R15 H, CH3 or C2H5; R1, R2, R3 and R4, which are the same or different,

(a) H;

(b) halogen;

(c) -CN;

(d) -CHO;

(e) -CF3;

O

® 11

(f) -C-R1;

O

Il 12

(g) -O-C-R;

(h) -CH (OR13) 2;

(i) - (Z) n-A-D;

© aryl;

(k) aryloxy;

(1) alkylthio of 1 to 6 carbon atoms;

(m) -NO2;

(n) alkylsulfinyl of 1 to 6 carbon atoms; or

(o) adjacent groups R1, R2, R3 and R4 together with the adjacent carbon atoms in the benzimidazole ring are a 5-, 6- or 7-membered monocyclic or a 9-, 10- or 1-membered bicyclic ring, these rings being saturated or unsaturated and zero can contain up to 3 heteroatoms from the group -N- and -O- and are optionally substituted 1 to 4 times, the substituents being those of alkyl having 1 to 3 carbon atoms and alkylene radicals having 4 to 5 carbon atoms, which are spiro compounds result, existing group is selected or two or four of these substituents together form one or two oxo groups, 0

V

(-C-),

where, when R1, R2, R3 and R4 together with the adjacent carbon atoms in the benzimidazole ring form two rings which can be condensed with one another, in which formulas R11 and R12 which are the same or different,

(a) aryl;

(b) alkoxy of 1 to 4 carbon atoms;

(c) alkoxyalkoxy having 1 to 3 carbon atoms in each alkoxy part;

(d) arylalkoxy having 1 to 2 carbon atoms in the alkoxy part;

(e) aryloxy;

(f) dialkylamino having 1 to 3 carbon atoms in the alkyl moieties; or

(g) pyrrolidino or piperidino, optionally substituted with alkyl of 1 to 3 carbon atoms;

R13 (a) alkyl of 1 to 4 carbon atoms; or

(b) alkylene of 2 to 3 carbon atoms;

9

Z -0- or -C-;

n zero or 1;

A (a) alkylene of 1 to 6 carbon atoms;

(b) cycloalkylene of 3 to 6 carbon atoms;

(c) alkenylene of 2 to 6 carbon atoms;

(d) cycloalkenylene of 3 to 6 carbon atoms; or

(e) alkynylene of 2 to 6 carbon atoms; and D (a) -CN;

(b) - <!> R9;

0

II in

(c) - (Y) - (C) - R

represent m r, where

R9 (a) alkoxy of 1 to 5 carbon atoms; or (b) dialkylamino having 1 to 3 carbon atoms in the alkyl moieties;

m zero or 1;

r zero or 1;

Y (a) -0-;

(b) -NH-;

(c) -NR10-;

R10 (a) H;

(b) alkyl of 1 to 3 carbon atoms;

(c) arylalkyl having 1 to 2 carbon atoms in the alkyl part; or

(d) aryl; and R5 (a) H; or

. O

represent where

R14 (a) alkyl of 1 to 6 carbon atoms;

(b) arylalkyl having 1 to 2 carbon atoms in the alkyl part;

(c) aryl;

(d) alkoxy of 1 to 4 carbon atoms;

(e) arylalkoxy having 1 to 2 carbon atoms in the alkyl part;

(0 aryloxy;

(g) amino;

(h) mono- or dialkylamino having 1 to 4 carbon atoms in the alkyl part or in the alkyl parts;

(i) arylalkylamino having 1 to 2 carbon atoms in the alkyl part; and

(j) arylamino;

represent; R6 and R8, which are the same or different,

(a) H; or

(b) alkyl of 1 to 5 carbon atoms; and R7 (a) H;

(b) alkyl of 1 to 8 carbon atoms;

(c) alkoxy of 1 to 8 carbon atoms;

(d) alkenyloxy of 2 to 5 carbon atoms;

(e) alkynyloxy of 2 to 5 carbon atoms;

(f) alkoxyalkoxy having 1 to 2 carbon atoms in each alkoxy group;

(g) dialkylaminoalkoxy having 1 to 2 carbon atoms in the alkyl substituents attached to the amino nitrogen and 1 to 4 carbon atoms in the alkoxy group;

(h) oxacycloalkyl having one oxygen atom and 3 to 7 carbon atoms;

(i) oxacycloalkoxy with two oxygen atoms and 4 to 7 carbon atoms;

(j) oxacycloalkylalkyl having one oxygen atom and 4 to 7 carbon atoms;

(k) oxacycloalkylalkoxy having two oxygen atoms and 4 to 6 carbon atoms; or

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

7

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(1) R6 and R7 or R7 and R8 together with the adjacent carbon atoms in the pyridine ring form a ring, the part formed by R6 and R7 or R7 and R8 -CH = CH-CH = CH,

-0- (CH2) p-,

-CH2 (CH2) p - O-CH = CH - NH-CH = CH- or

-N-CH = CH-

corresponds to, where p is 2, 3 or 4 and the O and N atoms are always bound to the 4-position of the pyridine ring,

mean, and the physiologically acceptable salts of compounds of formula I, wherein X is S;

with the requirements

(a) that only one of the symbols R6, R7 and R8 represents hydrogen;

(b) that when X is SO, R5 H and Rä, R7 and R8 is only hydrogen, methyl, methoxy, ethoxy, methoxyethoxy or ethoxyethoxy and at the same time more than one of the symbols R1, R2, R3 and R4 is hydrogen, of R1, R2, R3 and R4 at least one is not selected from alkyl, halogen, alkoxycarbonyl, alkoxy or alkanoyl,

(c) that when X S, R5 H, alkanoyl or alkoxycarbonyl and R6, R7 and R8 only hydrogen, methyl, ethyl, methoxy,

Mean ethoxy, methoxyethoxy or ethoxyethoxy and at the same time mean more than one of the symbols R1, R2, R3 and R4 are hydrogen, of R1, R2, R3 and R4 at least one not from alkyl, halogen, alkoxycarbonyl, alkoxy, alkanoyl,

5 trifluoromethyl or -NO2 is selected;

(d) that when X SO, one of the symbols R6, R7 and R8 is hydrogen and the other two of the symbols R6, R7 and R8 are alkyl and at the same time more than one of the symbols R1, R2, R3 and R4 is hydrogen, from those

10 radicals R1, R2, R3 and R4, which are not hydrogen, at least one not from alkyl, halogen, cyano,

0 0

-C- (alkoxy), (alkyl) -OC- (alkyl) -,

15 alkoxy, hydroxyalkyl, -CF3 or (alkyl) -C-

is selected; and

(e) that when R3, R4, R5 and R15 are hydrogen and simultaneously R6 and R8 are H or CH3 and R7 are -OCH3, R1

20 does not represent -CF3 when R2 is hydrogen and R2 does not represent -CF3 when R1 is hydrogen.

Examples of the various radicals in formula I are those listed below. These illustrative examples are based on the various

25 radicals depending on the number of the number of carbon atoms prescribed for each radical. “Alkyl” and “alkoxy” mean straight-chain, branched and cyclic structures.

Halogen:

F, Cl, Br, J

Alkyl:

Ch3 »C ^ Hg, nC ^ H- ,, iC ^ H ^, nC ^ Hg, sec.-C ^ Hg, iso.-C ^ Hg, tert.-C ^ Hg, nC ^ H- ^, n- CgH, - ,,

'• CH

'CH.

-CH

• Ch.

^^ - * CH_- CH., 1 ', -CH CH_, -CH I

Ch'2 ^ -CH2 / "^ ~ -CH2-CH2,

^ • CH, ^ (CH7) V, -Ch I 2, -CH 2 ^ H ^ 'Ch. 1/

^ (ch2) -2

Alkylene

-CH--, -ch2CH2-, -CCH2) ^ -. -CH2-CH - CCrt2J5-, -CCH2) 6- CH3

Cycloalkylene

-CH / CH-

^ -CHi z

/ CH23 2 \

-CH CH-,

n ^ ch -. '^'

(CH,] -,

/ 2nd

-CH CH-

\ GH2) 2

Alkenylene: -CH = CH-, -CH2 "CH = CH-, -CH ^ -CH = CH-Ch _ / -, - (uh2) 2-CH = CH-CH2-, - (Ch-2) 3-CH = Ch-Cn2-

Alkyltnio:

-S-CH3, -S-C2H5, -S-i-C3H7

^^ - CH = CH ^ CH-QH2

CycloalKenylene: - £ h "I, -C

CH -.- CH— ^ »CH., - CH.,

2 2

Alkynylene:

-C = C-

-ch2-c = c-

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Alkoxy:

-0CH3, -0C2H5, -0-n-C3H7, -0-i-C3H7, -ü-nC ^ Hg, -0-iso-C4Hg, -O-sec.-C ^ Hg, -O-tert.- C ^ Hg, -QnC ^ H ^,

^ ch-, -üch_-Ch '

• ch.

-ch.

^ ■ ch7ch7 -üch7ch7ch, -ch i

"^ • CH2CH2

: h7ch -o-CH z ch. H2ch ^ "~ '

Alkoxyalkoxy

-och, 2och3, -0ch2ch20ch3, -0ch2ch2qch2ch3 -0ch2ch2ch2cch2ch2ch3 r? i]

Ary 1:

// V

Arylalkoxy: -GCH2

7 V

, -0ch2ch2-

// v

Aryloxy:

-0-

// v

Arylalkyl:

Alkenyloxy: Alk inyloxy:

■ lH.

CH.

// \\

- C CH_} 2

V v

~ 'h "W

-0-CH = CH2, -0-CH = CH-CH3, -0-CH = CH-C2H5, -0-CH2-Ch = CH-Ch2CH3

- □ -c-ch, -o-ch2-c = ch, -o-Ch2-c ^: - ch3

-q-ch0-csc-ch_ch

Examples of the radical -CH (OR13) 2 are:

2 3

-ch yOCHg> -0C-, Mr.

\

-CH

'OCH-o

, 0-Cn.

/ UL2H5 X ° C2H5

-ch

^ 0Ch2CH2CH3

\

-CHS

-0-CH.

• och2ch2ch3

\ n-

0-CH.

/ U-Lnx

-CHîf * L) n_ TI-CH- / ^

Examples of ring structures including R1, R2, R3 or R "are:

666 892

where K

-CH2CH2CH2 - CH2CH2CH2CH2-

-CH2-C (CH3) 2-CH2-

- (CH2) 5-

-CH = CH-CH = CH-

CH3

- £ h-ch2ch2-

CH3

-CH2 "/: H-Ch2 - CH -CH -CH 3 CH3

2 "CH2"

CH -CH -CH -CH-

ÎH

3 ch3 ch3 ch3 -1CH2 J2 "Nn-

-och2o-

-0Ch2CH20-

-d-c (ch3) 2-o - 0 (ch2) 30-

ch_ ch_

1212

C ^ 2 f * 2

C - C - 0 --CH2-0- (CH2) 2-0-

-CH _, - 0-CH-CH -, - 0-2 I 2 CH,

CD-

20th

30th

35

40

45

50

The group - (Z) n - A - D has the following radicals, where “alkyl l-2c”, “alkyl l-3c” etc. each mean alkyl groups with the number of carbon atoms indicated.

A - CN

0 II

A - C - 0 - (alkyl l-5c) 0 ^ / (alkyl l-3c)

55

60

A - C

^ alkyl l-3c)

A - h

A 1 (alkyl l-3c) A - (alkyl l-2c) aryl A - aryl

A - 0 - H

A - 0 - (alkyl l-3c)

A - 0 - (alkyl l-2c) aryl

A - 0 - aryl

A - NH - H

A - NH - (alkyl l-3c)

A - NH - (alkyl l-2c) aryl

A - NH - aryl

R10 I

A - N - H R10

A - N - (alkyl l-3c)

R10 I

A - N - (alkyl 1-2c) aryl

? 10

A - N - aryl

0 II

A - 0 - C - H '

D 0

A- 0 - C - (alkyl l-3c)

0 II

A- 0 .- C - (alkyl l-2c) aryl

0 II

A- 0 - C - aryl

0

il

NH - C

H

y

A- NH - C - (alkyl l-3c)

A- NH - C - (alkyl l-2c) -aryl a- nh -

R10 0 I II A- N - C ■

R10 0

aryl

A - N - C - (alkyl l-3c)

R10 0 I II

A - N - C - (alkyl l-2c) aryl

P10, 9 '

-0 -A - CN

0

1

-0 -A - C-0- (alkyl 1-5c)

0 II

-o -A - c - N;

. (alkyl l-3c) '(alkyl l-3c) -0-A-H

-0-A - (alkyl l-3c) -0-A- (alkyl l-2c) -aryl -O-A-aryl

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10th

- A - 0 - H

-0 - A - 0 - (alkyl l-3c)

-0-A-0 - (alkyl l-2c) -aryl

-0-A-0-aryl

-0-A-NH-H

-G-- A - NH - (alkyl l-3c)

-0 - A - Nh - (alkyl l-2c) aryl

-0 - A - NH - aryl r.10

-0 - A - N - H

f10

-0 - A - N - (alkyl l-3c)

10th

-0 - A - N - (alkyl l-2c) aryl

.10

-0

A - l -

aryl

0 II

-Q - A - 0 - C - H 0

-0 - A - 0- t - (alkyl l-3c)

0

-0 - A - 0- C - (alkyl l-2c) aryl

S?

-0 - A - 0- C - aryl

-0-A-NH-H-H

-0-A

-0-A -0 - A

- NH - C - (alkyl I-3c) I - (alkyl I-I

- NH

(alkyl 1-2c) aryl

- NH - aryl

R10 0.

-0 - A - N

- I - H

-0-A -0-A

-0 - A

0 II

-C- A

0 II

-C- A

0 II

-C- A

R10 0

- N - C - (alkyl l-3c)

f10 9

- N - C - (alkyl l-2c) aryl

R10 0

- N - C -aryl

-CN

0 II

C - 0- (alkyl 1-5c) ö / (alkyl 1 -3c)

-C - N

20th

25th

30th

35

45

50

55

65

-C -A -H

0

-E -A

0 fl

-C -A

(alkyl l-3c)

(alkyl l-2c) aryl

■ C-aryl

0 II

-C -A

0 II

-C -A

0 II

-C -A

0 II

-C -A

y

-C -A

0 II

-C -A

0 II

-C -A

0

II

-C -A

0 II

-C -A

0 left

-C -A

ï

-C -A

-0 -H

-0- (alkyl l-3c)

-0 - (alkyl l-2c) aryl

-0 -aryl

■ NH -H

-NH - (alkyl l-3c)

-NH - (alkyl l-2c) aryl

-NH -aryl

F10

-N -H

R10 I

-N - (alkyl l-3c)

R10 I

-N - (alkyl l-2c) -aryl f10

-C -A -N -aryl

-C-A-O-C-H

8 p

-C-A-O-C- (alkyl 1-3C)

0 0 Il II

-C-A-O-C- (alkyl 1-2C) aryl

-C-A-O-C-aryl

0 0

Il II

-C-A-NH-C-H

\

'(alkyl l-3c)

11

o o

-C-A-NH-C- (alkyl 1-3C)

° S

-C-A-NH-C- (alkyl 1-2C) aryl

-C-A-NH-aryl

0 R10 0 II I H -C-A-N - C-H

0 R10 0 -C-A-N - C- (alkyl 1-3C)

0 R10 0

-C-A-N - C- (alkyl 1-2C) aryl

0 f p

Il 1 l -,

-C-A-N - C-aryl 0

The group . ^ ^ i 1 contains the following residues:

to

20th

25th

0 - {■

aryl

-C-0- (alkyl 1-4CJ Q

-C-D- (alkyl 1-3 c) -0- (alkyl l-3c) 0

if

-C-0- (alkyl l-2c) aryl

0 II

-C-0-ary1

/ (alkyl, l-3c>

-C-N.

45

50

Ü / —i

- C - N optionally substituted with alkyl

55

0

Il / - \

- C - N) optionally substituted with alkyl

60

0

-D-è

666 892

-0- (alkyl l-3c) -0- (alkyl l-3c)

-0-C- (alkyl 1-2c) aryl

-O-C-O-aryl

° / (alkyl l-3c)

-0-C-N

(alkyl l-3c)

-o-t-NQ optionally substituted with alkyl

G

.- 0 - C - N / optionally substituted with alkyl 0

The group _ ç _ r 4 contains the following residues:

0

; |

-C- (alkyl 1-6c)

0

-C- (alkyl l-2c) aryl 0

-ö-aryl 0

-C-0- (alkyl 1-4c)

0

-C-0- (alkyl l-2c) aryl

0 il

-C-O-aryl O

-l-NH-,

0

NH (alkyl 1-4c)

| j / (alkyl 1 -4c) - C - NC

(alkyl l-4c). (alkyl l-2c)

-C-N

-l aryl

NH (aryl)

Il 12

The group -O-C-R contains the following residues: alkyl sulfinyl: SOCHg, SOCgHg, SOCHgCHgCH-j, S0-i-C3H7,

0 n

-O-C-aryl 0

-0-C-0- (alkyl 1-4c)

65

Other examples of radicals in Formula I are:

S0CH3, S0C2H54 SOCHgCh SO-n-C ^ Hg, SO-n-CgH ^

oxacycloalkyl:

O-

666 892

12

oxacycloalkoxy: ^

-ch

Those of the compounds according to the invention which are present as sulfoxides (X = SO) have an asymmetric center in the sulfur atom, i.e. these compounds exist in the form of two optical isomers (enantiomers) or if they also have one or more asymmetric carbon atoms, then these compounds have two or more diastereomeric forms, each of which exists in two enantiomeric forms. Such asymmetric carbon atoms can be the carbon atom to which R15 is attached (if R15 is other than hydrogen) or a carbon atom in some of the substituents.

Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and uneven mixtures of the two fall within the scope of the present invention. Likewise, all possible diastereomeric forms (pure enantiomers or racemic mixtures) fall within the scope of the invention.

Those of the compounds according to the invention which are present as sulfides (X = S) can be asymmetric due to one or more asymmetric carbon atoms, as described above. The various possible diastereomeric forms as well as the pure enantiomers and racemic mixtures fall within the scope of the invention.

It should be noted that for all compounds according to the invention in which R5 is hydrogen, the substituents R1 and R4 as well as R2 and R3 are considered equivalent. This is due to the tautomerism in the imidazole part of the benzimidazole nucleus, which causes a balance between the two possible> NH forms.

The following example explains this:

ch3

1. Preferred groups of the radicals R1, R2, R3 and R4 are:

LH

2. Halogens, F, Cl, Br, furthermore the groups CN, CHO, CO (aryl), COO (alkyl), CFa, SCHs, SOCHs and NO2

3. the groups alkylene-D, O-alkylene-D and CO-alkylene-D, where D is CN, COO (alkyl), COR10, OR10 or R '°,

4. Aryl and aryloxy

^ 0-

6. -CH2CH2CH2-, -CH2CH2CH2CH2- and -CH = CH-CH = CH-

7.

-CH = CH-CH = C- (CH2) 2_3-

8. saturated heterocyclic ring structures with two oxygen atoms

9. unsaturated membered heterocyclic ring structures with one nitrogen atom.

15 II. Further preferred groups of the radicals R1, R2, R3 and R4 ind:

1. H

2. Halogens, such as Cl and Br, and the groups CO (phenyl), COOCHs, CF3, SCHs and SOCH3

3. alkyl, alkoxyalkyl, aryloxyalkyl, arylalkyl and aryl

4. Alkoxy, alkoxyalkoxy, aryloxyalkoxy, arylalkoxy and aryloxy

5. Alkanoyl

6. -CH2CH2CH2-, -CH2CH2CH2CH2- and -CH = CH-25 CH = CH-

7. -CH = CH-CH = C- (CH2) 2_3 ~

8. saturated heterocyclic ring structures with two oxygen atoms in 4.5, 5.6 or 6.7 “catechol positions”.

e.g. (5,6 position as shown)

> 0

lì

40

III. Other preferred groups for the radicals R1, R2, R3 and R4 are:

1.H

2. Br and the groups COOCH3 and CF3

45 3. the groups CHs, C2H5, CH (CH3) 2, CH3OCH2CH2-, phenyl

4. the groups CH3O, CH3 (CH2) 60-, CH3OCH2O-, (Phenyl) -0CH2CH2CH20-, (phenyl) CH2CH20-, (phenyl) O-

5. the groups CH3CO-, C2H5CO-

50 6. -CH2CH2CH2-, -CH2CH2CH2CH2-

7. -OCH2O-

-0w 0-

ö

in the 5.6- "catechol position"

55 IV. Particularly preferred groups of the radicals R1, R2, R3 and R4 are:

H, COOCHs, CF3, CH3, C2H5, CH (CH3) 2, CH3O, -CH2CH2CH2-, -CH2CH2CH2CH2- and -OCH2O-

V. In a preferred embodiment, at least 60 three of the radicals R1, R2, R3 and R4 are different from hydrogen or at least form a ring.

VI. In another preferred embodiment, the radicals R1 and R2 form a ring structure.

VII. In another preferred embodiment, the radicals R2 and R3 form a ring structure.

VIII. In a preferred embodiment, at least three of the radicals R1, R2, R3 and R4 are different from hydrogen.

13

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IX. In a preferred embodiment, the radicals R1, R2, R3 and R4 are selected from the group consisting of H, halogen, CF3, alkyl and alkoxy.

X. According to a preferred embodiment, the radicals R1, R2, R3 and R4 are selected from the group consisting of H, alkyl and alkoxy.

XI. In a preferred embodiment, the radicals R1, R2, R3 and R4 are selected from H and alkyl.

XII. X has preferred meaning of S.

XIII. X has preferred meaning of SO.

XIV. R15 preferably means H.

XV. R5 preferably has the meaning of H, arylcarbonyl, alkoxycarbonyl, arylalkoxycarbonyl, dialkylaminocarbonyl and arylaminocarbonyl.

XVI. Further preferred meanings for R5 are H, phenylcarbonyl, methoxcarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, dimethylaminocarbonyl and phenylaminocarbonyl.

XVII. The meaning of H for the radical R5 is particularly preferred.

XVIII. Preferred examples of the radicals R6 and R8 are:

1. H, CHa, C2H5, C3H7 and CH (CH3) 2

2. Ring structures which are connected to position 4 of the pyridine ring.

XIX. Particularly preferred examples of the radicals R6 and R8 are H, CH3, C2H5 and ring structures which are linked to position 4 of the pyridine ring.

XX. Preferred examples of the radical R7 are:

1. H, CHs, C2H5

2. OCHs, OC2H5, OCH2CH2CH3, 0 (CH2) 3CH3,

och2-0, och2 - ^>

3. OCH2CH = CH2, OCH2C = CH

4.0CH2CH20CH3,

5. OCH2CH2N (CH3) 2

6. -CH = CH-CH = CH- bound to positions 3 and 4,

-CH = CH-CH = CH- bound to positions 4 and 5, 5 -CH2CH2CH2- bound to positions 3 and 4, -CH2CH2CH2- bound to positions 4 and 5, -CH2CH2CH2CH2- bound to positions 3 and 4 , -CH2CH2CH2CH2- bound to positions 4 and 5, -OCH2CH2- bound to positions 3 and 4, 10 -OCH2CH2- bound to positions 4 and 5, -OCH2CH2CH2- bound to positions 3 and 4, -OCH2CH2CH2- positions 4 and 5 are bound.

XXI. Preferred examples of the radical R7 are:

I.CH3

15 2.OCH3, OG1H5, OCH2CH2CH (CH3) 2

3. OCH2CH = CH2

4. 0CH2CH20CH3, OCH2-Ç>

20 5. -CH2CH2CH2- bound to positions 3 and 4, -CH2CH2CH2- bound to positions 4 and 5, -CH2CH2CH2CH2- bound to positions 3 and 4, -CH2CH2CH2CH2- bound to positions 4 and 5, -OCH2CH2- bound to positions 3 and 4, 25 -OCH2CH2- bound to positions 4 and 5, -OCH2CH2CH2- bound to positions 3 and 4, -OCH2CH2CH2- bound to positions 4 and 5.

XXII. Particularly preferred examples of R7 are CH3, OCH3, OCH2CH2CH (CH3>, _och r- \

30 ^ 0 '

-OCH2CH2CH2- bound to the 3- and 4- or the 4- and 5-position.

XXIII. Preferred pyridyl substitution patterns are:

OCH, 0C, Hc OCH0CH, CH (CHJ,

n © c '"" tr

CH.

OCH

CH

2 "0 'CH-

666 892

och

ch3 c2hs

14

och

I.

ch,

C2H5 '

ch ch

■ 3

CH3

ch,

lQ,

XXIV. Other preferred pyridyl substitution patterns 20 are:

ch och

a ch3 c2h ch,

9

ch,

ch,

9

ch.

ch.

ch-

CH3 \ ^ N / CH3 CH3V ^ -CH3

XXV. Yet other preferred pyridyl substitution patterns are:

och3 och3

"■ 'ìèr ™' ra

ch3 ch

och2ch = ch2

ch,

ch,

LO

* ir x

60

XXVI. Particularly preferred pyridyl substitution patterns are:

■ ch,

och3 och2ch = ch2

Ch3 ^ C "3 CH3V

15

666 892

OCH2CH = CH2

HSr

5 ^ rTH2x - <^ lOJ

H

wherein R2 is alkyl or alkoxy, preferably CH3, C2H5, CH (CH3> and OCH3, and X is S or SO. 10 Further explanatory examples of radicals in the formula I are listed in the examples and lists of specific compounds in the following description.

Illustrative examples of compounds that fall within the scope of the invention are listed in Table 15 below.

Table 1 Illustrative examples of compounds of the invention x

r15

r1

r2

r3

r4

r5

r6

r7

r8

s

(1

ch3

ch3

ch3

ch3

H

CH3

0ch2ch = ch2

ch3

so h

ch3

ch3

ch3

ch3

h ch3

ogh2ch = ch2

ch3

s h

ch3

ch3

cm3

ch3

h ch3

och3

ch3

so h

ch3

ch3

ch3

ch3

h ch3

och3

ch3

s h

ch3

ch3

ch3

h h

ch3

0ch2ch = ch2

ch3

so h

ch3

ch3

ch3

h h

ch3

och2ch = ch2

ch3

s h

ch3

ch3

ch3

h h

ch3

och3

ch3

so h

ch3

ch3

ch3

h h

ch3

och3

ch3

s h

ch3

ch3

h ch3

h ch3

0ch2ch = ch2

ch3

so h

ch3

ch3

h ch3

h ch3

och2ch = ch2

ch3

s h

ch3

ch3

h ch3

h ch3

och3

ch3

so h

ch3

ch3

h ch3

h ch3

och3

ch3

s h

ch3

ch3

h h

h ch3

och2ch = ch2

cll3

so h

ch3

ch3

h h

h ch3

och2ch = ch2

ch3

s h

h ch3

ch3

h h

ch3

0ch2ch = ch2

cii3

so h

h ch3

ch3

h h

ch3

och2ch = ch2

ch3

s h

ch3

h h

ch3

h ch3

och2ch = ch2

cii3

so h

ch3

h h

ch3

h ch3

och2ch = ch2

ch3

s h

ch3

h h

h h

ch3

och2ch = ch2

ch3

so h

ch3

h h

h h

ch3

och2ch = ch2

ch3

s h

h ch3

h h

h ch3

0ch2ch = ch2

ch3

so h

h ch3

h h

h ch3

0ch2ch = ch2

ch3

s h

h och3

h h

h ch3

och2ch = ch2

ch3

XXVII. In a preferred embodiment, two of the radicals R6, R7 and R8 form a ring structure, while the third of the radicals R6, R7 and R8 is H.

XXVIII. In a preferred embodiment, R15 and R5 are H, at least three of the radicals R1, R2, R3 and R4 are different from hydrogen and R6 and R8 are H or CH3 and R7 are CH3, OCH3 or OCH2CH = CH2.

XXIX. In a preferred embodiment, R15 and R5 have the meaning H, the radicals R1, R2, R3 and R4 form at least one ring structure and mean R6 and R8 H or CH3 and R7 CHs, OCHj or OCH2CH = CHa.

XXX. Of the compounds of formula I are those of the formula below

666 892

16

x r15

r1

r2

r3

r4

r5

r6

r7

r8

so h

h och3

h h

h ch3

0ch2ch = ch2

ch3

s h

h och3

h h

h ch3

ochgcsch ch3

so h

h och3

h h

h ch3

och2c = ch ch3

so h

h och3

h h

h ch3

0 (ch2) 3ch = ch2

ch3

so h

h och3

h h

h ch3

0 (ch2) 3ch3

ch3

s h

h och3

h h

h ch3

0ch (ch3) 2

ch3

so h

h och3

h h

h ch3

och (ch3) 2

ch3

s h

h och3

h h

h ch3

0c (ch3> 3

cii3

so h

h och3

h h

h ch3

0c (ch3) 3

cii3

s h

h och3

h h

h ch3

° o ch3

so h

h och3

h h

h ch3

0 ^>

ch3

s h

h och3

k h

h ch3

0ch2- <3

cli3

so h

h och3

h h

h ch3

och2- <3

ch3

s h

h och3

H

H

h ch3

0ch2 ~ <O

ch3

so h

h och3

H

h h

ch3

0ch2 <>

ch3

s h

h och3

H

h h

ch3

0 (ch2) 2n (ch3) 2

ch3

s h

h och3

H

H

h ch3

0 (ch2) 2n + h (ch3) 2Cr ch3

so h

h och3

h h

h ch3

0 (ch2) 2n (ch3) 2

cll3

s h

h och3

h h

h ch3

och2ch2ch (ch3) 2

ch3

so h

h och3

H

h h

ch3

och2ch2ch (ch3) 2

ch3

so h

h och3

h h

h h

0ch3

c2h.

s h

h och3

h h

h h

0 (ch2) 3ch3

c2ii,

so h

h och3

h h

H

H

0 (ch2) 3ch3

c2H,

so h

h och3

h h

h ch3

och2ch2ch2ch (ch3) 2

ch3

so h

ch3

och3

ch3

h h

h c2H5

ch3

so h

h och3

h h

h ch3

och2ch2ch2 - <(j}

ch3

so h

ch3

och3

ch3

h h

h ch (ch3) 2

ch3

s h

h och3

H

H

h h

- (ch2) 4-

so h

h och3

h h

H

H

- (ch2) 4-

s h

h och3

H

H

H

- (ch

2) 4-

h so h

h och3

h h

H

- (ch2) 4-

ii p

h h

och3

h h

h h

-o- (ch2) 3-

so h

h och3

h h

H

H

-o- (ch2) 3-

s h

h och3

H

h h

- {ch2) 2-o-

h so h

h och3

H

H

H

- {ch2) 2-o-

h s

h h

och3

H

h h

H

-ch = ch-ch = ch-

so h

h och3

h h

h h

-ch = ch-ch = ch-

s h

h och3

h h

H

-ch = ch-ch = ch-

H

17th

666 892

, 15th

o3 •

r6 r7

s

H

h so h

H

s h

h so h

h s

H

H

so h

h s

h h

so

H

H '

s h

h so h

h s

h h

so h

h s

h h

so h

h s

h h

so h

h s

h h

so h

h s

h h

so h

h s

h h

so h

h s

h h

so h

H

s

H

h so h

h s

h h

so h

h s

h h

so h

h s

h h

so h

h s

h ch.

so h

ch s

h h

so h

h s

h h

so h

h ch

✓On

/ ° 1 ch • "n-f ch (och3) 2 ch (och3) 2

cho cho ch = ch-cooc2hg ch = ch-cooc2h5 ch2ch2cooc2h5 ch2ch2cooc2h5

ch2ch2con (ch3) 2 ch2ch2con (ch3) 2 ch = ch-cn ch = ch-cn ch2ch2cn ch2ch2cn ch2ch2ch2oh ch2ch2ch2oh ch2ch2ch2ococh3 ch2ch2ch2ococh3

ch2ch2ch2n (ch3) 2

ch2ch2ch2n (ch3) 2

ch2ch2ch2nhcoc2h5

ch2ch2ch2nhcoc2h5

ch = ch-coch3

ch = chcoch3

ch2ch2coch3

ch2ch2coch3

h h h h h h h h h h h h h h h h h h h h h h h h ch3 ch3

h h h h h

h h h h h h h h h h h h h h h h h h h h h h h h h h h h h h

h h h h h h h h h h h h h h h h h h h h h h h h h h h h h ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

CH3

ch3

och3

CH3

ch3

och3

Cllj ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och2ch = ch2

ch3

ch3

0ch2ch = ch2

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

, ch3

666 892

18th

x r15

r1

r2

r3

s h

h ocm2ch2hg>

h so h

H

0ch2ch2- <g)

h s

h h

och2cn h

so h

h och2cn h

s h

H

0ch2c00c2h5

h so h

H

0ch2c00c2h5

h s

h h

och2ch2oh h

so h

h och2ch2oh h

s h

H

0ch2ch20c0ch2- (c ^

h so h

H

0ch2ch20c0ch2 - (^ o)

h s

h h

0ch2ch2nh2

h so h

h och2ch2nh2

h s

h h

och2ch2nhcoch (ch3) 2

h so h

H

0ch2ch2nhc0ch (ch3) 2

h s

h h

0ch2c0 - ^ 0)

h so h

H

0ch2c0 - (O)

h s

h h

coh§)

h so h

h c0- {0)

h s

h h

c0 (ch2) 30- {c)>

h so h

H

CO (CH2) 3OHJO)

h s

h h

-o h

so h

h o

h s

h h

c00ch2ch20ch3

ch3

so h

h c00ch2ch20ch3

ch3

s h

h c00ch2- ^ o>

ch3

so h

h c00ch2- <0>

ch3

s h

h ch2oh ch3

so h

h ch2oh ch3

s h

h ch20c0 - ((3}

ch3

so h

h ch20c0 - (0}

ch3

s h

h c00ch3

ch3

so h

h c00ch3

ch3

s h

h ch2ch2och3

h so h

h ch2ch20ch3

h s

h h

ch (ch3) 2

h so h

h ch (ch3) 2

h s

h h

c (ch3) 3

h so h

h c (ch3) 3

h s

h ch3

och3

ch3

so h

ch,

0ch,

ch,

h h

h h

h h

h h

h h

h h

h h

h h

h h

h h

h h

h h

h h h h h h h h h h h h h h h h

h h

h h

h h

h h

h h

h h

h h

h h

h h

h h

h h

h h

h h h h h h h h h h h h h h ch3

och3

ch3

ch3

och3

cii3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3 '

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

c "3

ch3

och3

ch3

ch3

och3

cii3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och2ch = ch2

ch3

ch3

och2ch = ch2

ch3

ch3

och3

cii3

ch3

och3

ch3

ch3

och2ch = ch2

ch3

ch3

och2ch = ch2

ch3

ch3

och2ch = ch2

ch3

ch3

och2ch = ch2

ch3

ch3

och3

ch3

ch3

och3

ch3

19th

666892

x r15

r1

r2

r3

r4

r5

r6

r7

r8

s h

ch3

och3

ch3

h h

ch3

ch3

ii so h

ch3

och3

ch3

h h

ch3

ch3

h s

h ch3

och2ch2och3

ch3

h h

ch3

och3

c »3

so h

ch3

0ch2ch20ch3

CH3

h h

ch3

och3

ch3

s h

ch3

och2ch2och3

ch3

h h

h ch3

ch3

so h

ch3

och2ch2och3

ch3

h h

h ch3

ch3

s h

ch3

coch3

ch3

h h

ch3

och3

ch3-

so h

ch3

coch3

ch3

h h

ch3

och3

CII3

s h

ch3

coch3

ch3

h h

ch3

h cll3

so h

ch3

coch3

ch3

h h

ch3

h cll3

s h

ch3

coc2hg ch3

h h

ch3

och3

ch3

so h

ch3

coc2hg ch3

h h

ch3

och3

ch3

s ch3

ch3

ch3

ch3

h h

ch3

och3

ch3

so ch3

ch3

ch3

ch3

h h

ch3

och3

ch3

s h

ch3

ch3

ch3

h h

ch3

ch3

ch3

so h

ch3

ch3

ch3

h h

ch3

ch3

ch3

s h

ch3

C2H5

ch3

h h

ch3

och3

ch3

so h

ch3

C2H5

ch3

h h

ch3

och3

ch3

s h

ch3

C2H5

ch3

h h

ch3

och3

h so h

ch3

c2h5

ch3

h h

ch3

och3

h s

h ch3

ch (ch3) 2

ch3

h h

ch3

0CH3

ch3

so h

ch3

ch (ch3) 2

ch3

h h

ch3

0CH3

cll3

s h

ch3

ch (ch3) 2

ch3

h h

ch3

ch3

ch3

so h

ch3

ch (ch3) 2

ch3

h h

ch3

ch3

ctl3

s h

ch3

cogh2H ^

ch3

h h

ch3

och3

ch3

so h

ch3

COCH2- <g)

ch3

h h

ch3

och3

ch3

s h

och3

Br

0CH3

h h

ch3

och3

ch3

so h

och3

Br

0ch3

h h

ch3

och3

ch3

s h

och3

Break 3

h h

ch3

ch3

h so

H

och3

Break 3

h h

ch3

ch3

h s

H

C2H5

cn c2H5

H

h ch3

0CH3

ch3

so h

c2h5

cn c2h5

H

H

ch3

0CH3

ch3

s h

c2h5

cn c2h5

H

H

ch3

oc2H5

ch3

so h

c2h5

cn c2h5

H

H

ch3

oc2H5

ch3

s h

ch3

OCH3

ch3

ch3

h ch3

OCH3

ch3

so h

ch3

och3

ch3

ch3

h ch3

0CH3

cl <3

s h

ch3

och3

h ch3

h ch3

0CH3

c.l3

so h

ch3

0CH3

h ch3

h ch3

och3

dl3

s h

Cl

OCH3

h och3

h ch3

och3

ch3

so h

Cl

0ch3

H

och3

h ch3

och3

ch3

892 20

X R15 R1 R2 R3 R4 R5 R6 R7 RU

S

H

Cl c1

Cl h

h ch3

och3

ch3

so

H

Cl

Cl

Cl h

h ch3

0ch3

ch3

s

H

Cl

Cl

Cl h

h ch3

och2ch = ch2

ch3

so

H

Cl cl cl h

h ch3

och2ch = ch2

ch3

s

H

Cl

Cl

Cl

Cl h

ch3

och3

CH3

so

H

Cl

Cl

Cl

Cl h

ch3

och3

ch3

s h

Cl

Cl

Cl

Cl h

ch3

och2ch = ch2

ch3

so

H

Cl

Cl cl

Cl

H

ch3

och2ch = ch2

ch3

s h

0CH3

Br

H

och3

h ch3

och3

ch3

so h

OCH3

Br h

och3

h ch3

och3

ch3

s

H

0CH3

Cl

Cl oc2h5

H

ch3

och3

ch3

so h

0CH3

Cl

Cl

0C2H5

h ch3

0CH3

ch3

s h

0CH3

Cl

Cl

0C2H5

h ch3

ch3

h so h

0CH3

Cl

Cl

0C2H5

h ch3

ch3

H

s h

COCH3

ch3

ch3

ch3

h ch3

och3

ch3

so h

COCH3

ch3

ch3

ch3

h ch3

0ch3

ch3

s h

F

Cl h

Cl h

ch3

och3

CH3

so h

F

Cl h

Cl h

ch3

och3

ch3

s h

Cl ch2c00ch3

Cl h

h ch3

och3

ch3

so h

Cl ch2c00ch3

Cl h

h ch3

och3

ch3

s h

Cl ch2cn

Cl h

h ch3

0CH3

ch3

so h

Cl ch2cn

Cl h

h ch3

0CH3

ch3

so h

-ch = ch-

• ch = ch-

-ch = ch-

-ch = ch-

h ch3

0CH3

ch3

ch,

s h

H

COnj>

h h

h ch3

0CH3

ch3

ch3

so h

H

COf / ~ \

h h

h ch3

OCH3

ch3

s h

H

h h

h ch3

0ch3

ch3

so h

H

h h

h ch3

och3

ch3

s h

H

-0ch20-

h h

ch3

och3

CII3

so h

H

-och2o

-

h h

ch3

och3

ch3

s h

H

-och2o

-

h h

ch3

ch3

ch3

so h

H

-och2o

-

h h

ch3

ch3

CII3

s h

h y

-0 0

1-

h h

ch3

och3

ch3

so h

H

- <pc

1-

h h

ch3

och3

ch3

s h

-ch = ch-ch = n-

h h

h ch3

och3

ch3

so h

-ch = ch-ch = n-

h h

h ch3

och3

ch3

s h

-ch = ch-ch = ch-

h h

h ch3

0CH3

ch3

21st

666 892

, 15th

so s so s so

-ch = ch-ch = ch-

-ch = ch-ch = ch - ch = ch-ch = ch-

-ch2ch2ch2ch2 - ch2ch2ch2ch2-

S

h och3

SO

h och3

s h

och3

so h

och3

s h

-

so h

-

s h

h so h

h s

h h

so h

h s

h h

so h

h s

h h

so h

h s

h h

so h

h s

h h

so h

h s

h h

so h

h s

h h

so h

h s

h h

so h

h s

h h

so h

h s

h h

so h

h s

h ch3

so h

ch3

s h

h so h

h s

h h

ch = ch ch3

ch3

och3

och3

oh

"CO-

c0-

-och2o - ücii20--0ch20-

-och2o - och2o - och2o - och2o-

-och2o - och2o - och2o - och2o - och2o - och2o - och2o - och2o - och2o - och2o-

-ochgo - 0ch20-

-och2o-

-ch2ch2ch2 - ch2ch2ch2 - ch2ch2ch2 - ch2ch2ch2-ch = c - ch2ch2

2 2

ch3 ch3

h h h h h h h h

Cl

Cl

Cl

Cl h

h h h h h h h h h h h h h h h h h h h h h h h h h h h h h h h h

co2ch3 co2ch3

C02C2H5 COgC-jHg co2c (ch3) 3

co2c (ch3) 3 - ©

c02ch2

co2ch2- <0> co co conh2 conh2 conhc2h5 conhc2h5

conhchg conhch-

.- <o> com- (o)

conh- ^ ö)

c0n (ch3) 2

c0n (ch3) 2

h h

h h

h ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

oc2h,

ch3

oc2h (

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

• ° ch3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och3

ch3

och2i ch3

0ch2i

-ch = ch-0 - ch = ch-0-

ch3 ch,

ch,

ch,

ch,

ch3

ch,

ch,

ch,

ch,

Cil,

cl !,

ch,

ch,

ch,

ch,

ch,

ch,

ch3

ch,

ch3 ch3 ch3 ch3 ch3 ch3

cll3 ch3

ch3 ch3 ch3 ch3 ch3 ch3 ch3

h h

-0-ch = ch-

666 892

22

, 15th

so h

h s

h h

so h

h s

h h

so h

h s

h h

so h

h s

h h

so h

h s

h ch.

so h

ch.

s h

h so h

h s

h h

so h

h s

h ch.

so h

ch s

h h

so h

h s

h h

s h

h so h

h so h

h s

h h

s h

h s

h h

so h

h so h

h s

H

so h

s h

h s

h h

so h

h s

h h

so h

h so h

h s

h h

0ch3 och3 och3 och3 och3 och3 och3

0ch,

0ch3 ch2c5ch ch2c = ch ch2ch2ch2 CHzch2ch2

0ch2ch2ch20 0ch2ch2ch20

0 (ch2) 6ch3 0 (ch2) 6ch3

c2h5 c2h5

och3

h och3

h ch,

0-® - ©

ch2oco ch,

-0ch20 - och2o-

-oc co-

n

-oc co-

sh

ch (ch3) 2

ch (ch3) 2

ch2ch2coch3 ch2ch2coch3 ch,

ch,

h h h h h h h h h ch3 ch3

h h h h ch3 ch3

h h h och3

h och3 ch2oco ch,

ch,

h h ch3

ch,

h h

h h

h h

h h

h h

h h

h h

h h

h h

h h

h h

h h h h h h h h h h h h h h h h h h h h h h h h CO CO coco CO-

-0-ch = ch-

- ©

CO

©

<§>

COC2Hg coc2h5 cooch,

-ch = ch-nh - ch = ch-nh-

-nh-ch = ch - nh-ch-ch-

-ch = ch-n (ch3) - ch = ch-n (ch3) -

cooc (ch3) 3 con (ch3) 2

H

-n (ch3) -

-ch = ch-

H

-n (ch3) -ch = ch-

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och2ch = ch2

ch3

ch3

och2ch = ch2

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

cll3

ch3

och3

cll3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

och3

ch3

ch3

oh

ch3

ch3

/ —- \ «"! <"}

ch3

ch3

mzÇ>

ch3

ch3

och2ch = ch2

ch3

ch3

och2ch = ch2

ch3

ch3

och3

ch3

ch3

och3

ch3

23

666 892

, 15th

so h

h ch3

ch3

s h

H

Br h

so h

H

Br h

s h

ch3

ch3

ch3

so h

ch3

ch3

ch3

s h

ch3

ch3

ch3

so h

ch3

ch3

ch3

s h

ch3

ch3

ch3

so h

ch3

ch3

ch3

s h

ch3

ch3

h so h

ch3

ch3

h s

h ch3

cn ch3

so h

ch3

cn ch3

so

H

H

cooch3

ch3

s h

H

-ch2ch2ch2-

so h

H

-ch2ch2ch2-

so h

h och3

h so h

h och3

h s

h h.

so3

h so h

H

so3

h s

H

h ch3

ch3

so

H

H

ch3

ch3

s

H

-CH = CH

-ch = ch-

-ch so

H

H

no2

h s

H

H

CF3

h so

H

H

cf3

h s

h h

ch2ch2cooc2h5

h so

H

H

■ och3

h so h

h ch3

ch3

h h h h h h h h h ch3

ch3

h h

h h

h h

H

H

H

H

ch = ch-ch = ch-

con (ch3) 2

h h h h h h h h h h h h h h h h h ch3

och3

ch3

ch3

och2ch = ch2

ch3

ch3

0ch2ch = ch2

ch3

ch3

ch3

h ch3

ch3

h h

ch3

ch3

h ch3

ch3

ch3

H

Ctl3

ch3

H

CH3

ch3

ch3

h ch3

ch3

H

ch3

oc2h5

CH3

ch3

oc2h5

ch3

h och3

C2H5

ch3

. 0CH3

ch3

ch3

och3

ch3

-ch2ch2ch2o-

nc-OC (ch,) h

3 '3

H

ch3

och3

ch3

och3

ch3

-ochjp ch3

-ochjp ch3

° ch3

ch3

och3

ch3

OCHj-

ch3

ochg-

ch3

0ch3

ch3

och3

h och3

-och2ch2-

rO

ch,

ch,

ch-

ch,

ch,

ch,

ch,

ch,

CH,

ch,

C2H5

55

It is to be considered that compounds which differ structurally from those of the formula I are converted into a compound of the formula I after administration to a living organism and develop their action in this structural form. Such structurally different compounds from the compounds of formula I are included in the scope of the invention.

Similarly, certain compounds of formula I can be metabolized to other compounds of formula I before they take effect. It is believed that compounds according to the invention, in which X is S, only have their antisecretory and cell-protective activities after metabolism to give compounds in which

X has the meaning of SO, and that compounds according to the invention in which R5 has the meaning R14CO also develop their antisecretory and cell-protective activity after metabolism to give compounds in which R5 is H. These considerations represent another aspect of the invention.

Furthermore, it is assumed that all compounds of the formula I, in which X has the meaning SO,, after administration to a living organism, display their antisecretory and cell-protective effects after metabolism or purely chemical conversion into other reactive species. Correspondingly, this also applies to compounds of the formula I in which X has the meaning S, but on the way

60

65

666 892

24th

via an initial conversion to the corresponding compounds of formula I, wherein X represents SO. These considerations, as well as such reactive species as such, fall within the scope of the present invention.

Compounds of the formula I can be prepared by the following methods:

a) oxidation of a compound of formula I.

(I)

wherein X represents S and R15, R1, R2, R3, R4, R5, R6, R7 and R8 have the meanings given, to a compound of the same formula I, wherein X has the meaning SO. The oxidation can be carried out using an oxidizing agent, nitric acid, hydrogen peroxide, peracids, peresters, ozone, dinitrogen tetraoxide, iodosobenzene, N-halosuccinimide, 1-chlorobenzotriazole, t-butyl hypochlorite, diazabicyclo- [2,2,2] as the oxidizing agent. -Octane-bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, cerium IV ammonium nitrate,

Bromine, chlorine and sulforyl chloride come into consideration. The oxidation usually takes place in a solvent in which the oxidizing agent is present in a slight excess with respect to the product to be oxidized.

The oxidation can also be carried out enzymatically using an oxidizing enzyme or microbiologically using a suitable microorganism.

b) implementation of a compound of formula II

such as mesyloxy, alkyl mercapto groups e.g. Methyl mercapto, alkylsulfinyl groups, e.g. Methylsulfinyl, and like compounds.

If Z1 or Z2 denote cleavable groups, they can also be reactively esterified hydroxyl groups. The esterification can be carried out with an organic acid or with an inorganic acid, such as HCl, HBr or H2SO4.

The reaction of a compound of formula II with a compound of formula III is conveniently carried out in the presence of a suitable solvent which is inert under the reaction conditions used, as will be described below. The reaction can also be carried out in the presence of a suitable base. Suitable bases include, for example, inorganic bases such as sodium or potassium hydroxide, sodium or potassium alkoxide, sodium or potassium hydride and the like, and also organic bases such as tertiary amines, e.g. Triethylamine and similar compounds.

Suitable solvents for the above-described reaction include, for example, alcohols, preferably lower alkanols such as methanol and ethanol, mixtures of such alcohols with water, ethers such as tetrahydrofuran, halo-25 hydrocarbons such as methylene chloride. Aprotic solvents such as ether and halogenated hydrocarbons are important in the case of sodium and potassium hydride.

The reaction of the compounds of the formulas II and III 30 can be carried out at a temperature in the range between room temperature and the boiling point of the reaction mixture. However, the reaction is preferably carried out at a temperature at or near the boiling point of the reaction mixture when a compound 35 of the formula I in which R5 corresponds to H is prepared.

c) esterification of a compound of formula IV

40

with a compound of formula III

(II)

y2 (IV),

in these formulas R15, R1, R2, R3, R4, R5, R6, R7 and R8 have the meanings given and one of the groups Z1 and Z2 is SH and the other is a cleavable group in order to obtain a compound of the formula I. , where X has the meaning S. Examples of cleavable groups Z1 and Z2 in the compounds II and III are halogens, preferably chlorine, bromine or iodine, acyloxy groups, e.g. Residues of strong organic sulfonic acids, e.g. an arylsulfonic acid such as tosyloxy, or an alkylsulfonic acid,

wherein R13, R5, R6, R7 and R8 have the meanings given above and Y1, Y2, Y3 and Y4 represent either R1, R2, R3 and R4 according to the definition given above (III), 55 or the groups (Z) nA- COOH, COOH and (Z) nA-OH, where Z, n and A have the meaning given above, correspondingly by reaction with the corresponding x alcohol R9OH, RI0OH or the corresponding carboxylic acid R10COOH, to form a compound of the formula I which a Contains radical R1, R2, R3 and / or R4, which correspond to one of the ester groups (Z) "- A-COOR9, COOR10 or (Z) nA-OCOR10.

The esterification is carried out as an ordinary esterification reaction in the presence of an acid catalyst such as sulfuric acid, hydrochloric acid or p-toluenesulfonic acid, if necessary in the presence of an inert solvent such as toluene.

d) acylation of a compound of formula V

25th

666 892

- J »? '

k15 \ ÌU

wherein R15, X, R1, R2, R3, R4, R6, R7 and R8 have the meaning given above, by reaction with an acylating agent which consists of that of potassium isocyanate, (R14C0) 20 and R ^ COX1, wherein X1 is a cleavable group such as Cl, N3 or p-nitrophenoxy means formed group is selected, acylated to produce a compound of formula I, wherein R5 corresponds to the group RI4CO.

The acylation is preferably carried out in the presence of a base, such as triethylamine, K2CO3 or NaOH, and with a solvent, such as tetrahydrofuran, acetonitrile or water. When the benzimidazole moiety is asymmetrically substituted, both the N (l) and the N (3) acyl derivatives are normally obtained. If necessary, the two components are separated. This can be done by recrystallization or by extraction using chromatography.

e) hydrolysis of a compound of formula VI

2 (vi),

wherein X, R15, R1, R2, R3, R4, R6, R7 and R8 have the meaning given above and Z3 represents a suitable N-protecting group, such as alkanoyl, carbalkoxy or trimethylsilyl, to form a compound of Formula I, in which Rs has the meaning H.

Alkanoyl groups Z3 can have 1 to 6 carbon atoms and carbalkoxy groups 2 to 6 carbon atoms. The hydrolysis can be carried out in an alkaline or in an acidic solution, the latter being used mainly for compounds in which X has the meaning of S.

Subsequently, a compound of formula I obtained in which X has the meaning of -S- can, if desired, be converted into a physiologically acceptable salt or oxidized to a compound of formula I in which X has the meaning -SO-.

Depending on the process conditions and the starting materials, the end products of the formula I in which X is S are obtained in the form of the free base or as a salt. The end products of the formula I, in which X has the meaning -SO-, are obtained in the form of the free base. Both the free bases and the salts of these end products are encompassed by the invention. Basic, neutral or mixed salts can be obtained in the same way, such as hemi-, mono-, sesqui- or polyhydrates. Acid addition salts of the new sulfides can be prepared in a manner known per se using basic agents, e.g. Alkalis, or converted into the free bases by ion exchange. The free bases of the sulfides obtained can also form salts with organic or inorganic acids. In the preparation of acid addition salts, preference is given to using those acids which provide useful therapeutically acceptable salts.

5 Examples of such acids are hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid and per (V) chloric acid; aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as, for example, formic acid, acetic acid, propionic acid, succinic acid, gly-10-colic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, benzoic acid, phenobenic acid, phenobic acid, phenobic acid, phenylacetic acid, phenobic acid -zoic acid, p-hydroxybenzoic acid, salicylic acid or p-amino-salicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthylsulfonic acid or sulfanilic acids, arginine, methionine, lysinophynophynin, tryinophan, methionine lysinophyne

These or other salts of the new sulfide compounds, 20 e.g. Picrates can serve as a means of purifying the free bases obtained. One can proceed in such a way that salts of the bases are formed, separated from the solution and then the free base is obtained in higher purity from a new salt solution.

Racemates obtained can be separated by known methods, e.g. by recrystallization from an optically active solvent, use of microorganisms, reactions with optically active acids to form diastereomeric salts which can be separated off (for example 30 separation due to the different solubilities of the diastereomers), acylation of the benzimidazole nitrogen (R5 = H) or another nitrogen or oxygen atom in a substituent with the help of an activated optically active carboxylic acid (eg acid chloride), subsequent chromatographic separation and deacylation.

Suitable optically active acids for the formation of the salts are the L and D forms of tartaric acid, di-o-tolyl-tartaric acid, malic acid, mandelic acid, camphor sulfonic acid or quinic acid and for the acylation O-methylmandelic acid. The more active part of the two antipodes is preferably isolated.

In the case of diastereomeric mixtures (racemic mixtures), these can be separated into the racemates (diastereomers) which are pure in terms of stereoisomerism by means of chromatography or fractional crystallization. The starting materials used in processes a) and c) to e) are obtained using process b). The starting materials for process b) are known in some cases, but in most cases unknown. However, these unknown starting materials can be obtained by methods known per se. Starting materials of formula II

40

45

55

(ii),

where Z1 is SH, can be obtained from the corresponding 0-phenylenediamine by reaction with potassium ethyl xanthate (Órg. Synth. Vol. 30, page 56) or thiophosgene.

666 892

26

The compounds of the formula II in which Z1 denotes alkylmercapto or alkylsulfinyl can be obtained from the above-mentioned compound by simple S-alkylation with an alkyl halide or by oxidation of the product from the S-alkylation.

The compounds of the formula II in which Z1 is halogen or acyloxy can be obtained from compounds of the same formula in which Z1 is OH by treatment with POCh, POBn and similar compounds or the corresponding acid halides. The starting material, in which Z1 has the meaning of OH, can be obtained from the corresponding o-phenylenediamine by reaction with phosgene.

The required o-phenylenediamines can be obtained from the corresponding substituted benzenes by methods known per se, e.g. with the help of the reaction sequence: nitration, reduction, acetylation, nitration, deacetylation and reduction, or starting from one of the intermediates already mentioned. In order to obtain an o-phenylenediamine in which R5 is different from hydrogen, the acylation reaction (by the RI4CO group) is preferably carried out in the nitro-aniline stage.

Starting materials of formula III

(III),

where R15 is H, can either from the correspondingly substituted (R6, R7 and R8) 2-methyl-substituted pyridine-N-oxide via a known rearrangement to the intermediate 2-pyridinylmethanol or by hydroxymethylation of the substituted (R6, R7 and R8) pyridine to the same intermediate stage and subsequent treatment of the 2-pyridinyImethanol with halogenating agents, such as thionyl chloride, or O-acylating agents, such as p-toluenesulfonyl chloride, to give compounds of the formula III in which Z2 is halogen or a sulfonyloxy group, to obtain.

These cleavable groups can then be substituted to form corresponding alkyl mercapto groups, e.g. by treatment with sodium alkyl mercaptide, which can then be oxidized to an alkylsulfinyl group, or substituted by the group SH, e.g. by treating with NaSH.

For the preparation of intermediates of formula VII

The following intermediate stages A) and B) fall within the scope of the invention.

A. New compounds of formula VIII

10th

R R5s

(VIII),

wherein RIa, R2a, R3a and R4a are the same or different and have one of the following meanings:

.5 (a) H;

(b) alkyl of 1 to 6 carbon atoms, including cycloalkyl;

(c) alkoxyalkyl having 1 to 3 carbon atoms in the alkoxy part and 1 to 6 carbon atoms in the alkyl part;

20 (d) alyloxyalkyl having 1 to 6 carbon atoms in the alkyl part;

(e) arylalkyl of 1 to 6 carbon atoms in the alkyl part;

(f) aryl;

(g) alkoxy of 1 to 6 carbon atoms;

25 (h) alkoxyalkoxy having 1 to 3 carbon atoms in the outer part and 1 to 6 carbon atoms in the part closest to the aromatic ring;

(i) aryloxyalkoxy having 1 to 6 carbon atoms in the alkoxy part;

3o Ö) arylalkoxy with 1 to 6 carbon atoms in the alkoxy part; and

(k) aryloxy;

R5a (a) H;

(b) alkoxycarbonyl having 1 to 4 carbon atoms in the

35 alkoxy part;

(c) arylalkoxycarbonyl having 1 to 2 carbon atoms in the alkoxy part;

(d) dialkylaminocarbonyl having 1 to 4 carbon atoms in each alkyl group; or

40 (e) arylaminocarbonyl; and

Zla (a) SH;

(b) mean Cl or Br, with the proviso that only one of the symbols Rla, R2a, R3a and R4a represents hydrogen, suitable intermediate

45 stages for the preparation of compounds of the formula I in which R1, R2, R3, R4 and R5 have the same meaning as Rla, R2a, R3a, R4a and R5a, according to method b).

B. New compounds of formula IX

(VII),

wherein R7 is alkoxy, alkenyloxy, alkynyloxy, alkoxyalkoxy and dialkylaminoalkoxy, a compound of formula VII, wherein R7 is NO2, is reacted with the corresponding sodium alkoxide. In an analogous manner, for the preparation of an intermediate of formula VII, in which R6 and R7 or R7 and R8 form a ring structure which includes an oxygen atom in the 4-position, a compound of formula VII, in which R7 is NO2 and R6 or R8 is hydroxyalkyl, with implemented a non-nucleophilic base.

(IX),

wherein R6a and R8a (a) H or

(b) alkyl of 1 to 5 carbon atoms; and

R7a (a) alkenyloxy of 2 to 5 carbon atoms;

60 (b) alkynyloxy of 2 to 5 carbon atoms;

(c) oxacycloalkyl having one oxygen atom and 3 to 7 carbon atoms;

(d) oxacycloalkoxy having 2 oxygen atoms and 4 to 7 carbon atoms;

65 (e) oxacycloalkylalkyl having one oxygen atom and 4 to 7 carbon atoms;

(f) oxacycloalkylalkoxy with two oxygen atoms and 4 to 6 carbon atoms; or

27th

666 892

(g) R6a and R7a or R7a and R8a together with the adjacent carbon atoms in the pyridine ring form a ring, in which the part formed by R6a and R7a or R7a and R8a forms one of the groups -CH = CH-CH = GH-,

~ 0- (CH2) pa-,

-CH2- (CH2) pa-and -O-CH = CH-,

where pa is 2, 3 or 4 and the O atom is always bound to the R7a position; and Z2a (a) SH;

(b) halogen such as Cl, Br, J; or

(c) OH;

mean, provided that only one of the symbols R6a and RSa is hydrogen, are suitable intermediates for the preparation of compounds of the formula I in which R6, R7 and R8 have the same meaning as R6a, R7a and R8a, according to method b).

For clinical use, the compounds according to the invention are made up into pharmaceutical preparations for oral, rectal, parenteral or other dosage forms. The pharmaceutical preparation contains a compound according to the invention in combination with a pharmaceutically acceptable carrier. The carrier can be in the form of a solid, semi-solid or liquid diluent or as a capsule. These pharmaceutical preparations represent a further subject of the invention. The proportion of active compounds is usually 0.1 to 95% by weight, based on the preparation, and specifically between 0.2 to 20% by weight in the case of preparations for parenteral use Use and between 1 to 50 wt .-% in preparations for oral administration.

When packaging pharmaceutical preparations containing a compound according to the invention in the form of dosage units for oral administration, the selected compound can be mixed with a solid powdered carrier, such as lactose, sucrose, sorbitol, mannitol,

Starch, amylopectin, cellulose derivatives or gelatin, or another carrier as well as with lubricants, such as magnesium stearate, calcium stearate, sodium steryl fumarate and polyethylene glycol waxes. The mixture is then processed into granules or pressed into tablets. Since the sulfoxides according to the invention are susceptible to degradation in acidic to neutral media, granules and tablets which contain sulfoxides are preferably provided with an enteric coating which protects the active component from degradation by acid as long as the dosage unit remains in the stomach. The enteric coating is selected from pharmaceutically acceptable enteric coating materials such as beeswax, shellac, or anionic film-forming polymers such as cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, partially methyl esterified methacrylic acid polymers, and similar materials, if desired in combination with a suitable plasticizer. Various dyes can be added to this coating to enable a distinction to be made between tablets or granules with different active compounds or with different contents of the active component present.

In the production of soft gelatin capsules, a mixture of one or more of the active compounds according to the invention and vegetable oil, fat or other suitable vehicles for soft gelatin capsules is introduced into them. Soft gelatin capsules can also be provided with an enteric coating, as described above. Hargelatine capsules can contain granules or granules of the active compound provided with an enteric coating. Hard gelatin capsules can also contain the active compound in combination with a solid powdered carrier, such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. The hard gelatin capsules can be provided with an enteric coating as described above.

Dosage units for rectal use can be in the form of suppositories containing the active substance in admixture with a neutral fat base, or in the form of a gelatin rectal capsule containing the active substance in admixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal Contain capsules or in the form of a ready-made micro-enema or in the form of a dry micro-enema preparation, which is reconstituted with a suitable solvent immediately before administration.

Liquid preparations for oral administration can be prepared in the form of a syrup or a suspension, e.g. in the form of solutions or suspensions which contain 0.2 to 20% by weight of the active ingredient, the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations can contain colorants, flavoring agents, saccharin, carboxymethyl cellulose or other thickening agents. Liquid preparations for oral administration can also be prepared in the form of a dry powder, which is reconstituted with a suitable solvent before use.

Solutions for parenteral administration can be prepared as a solution of a compound according to the invention in a pharmaceutically acceptable solvent, preferably in a concentration of 0.1 to 10% by weight. These solutions can also contain stabilizing agents and / or buffers and can be filled into ampoules or violas in different individual doses. Solutions for parenteral administration can also be packaged as dry preparations which are to be reconstituted immediately before use.

The daily doses of the active compound to be used in individual cases can be varied within a wide range and depend on various factors, such as, for example, the individual need of the individual patient, the route of administration and the disease. In general, the daily dose for oral and parenteral administration ranges from 5 to 500 mg of active substance per day.

The following examples serve to illustrate the invention.

example 1

Method a) Preparation of 4,6-dimethyl-5-methoxy-2 - [[(3,4-dimethyl-2-pyridinyl) methyl] sulfinyl] -1 H-benzimidazole

0.53 g (0.0028 mol, 91%), dissolved in 25 ml of CH2Ch and cooled to -10 ° C., were stirred with 0.91 g (0.0028 mol) of 4,6-dimethyl-5- methoxy-2 - [[(3,4-dimethyl-2-pyridynyl) methyl] thio] -1 H-benzimidazole, dissolved in 50 ml of CH 2 Cl 2, while maintaining the temperature at -5 ° C. Stirring at -5 ° C was continued for 5 minutes, after which 0.34 g (0.0085 mol) of NaOH dissolved in 25 ml of water was added with vigorous stirring. The two phases were separated and the aqueous phase was washed out with 10 ml CH2Ch. Then a further 50 ml of CH2C12 were added to the aqueous phase, the pH was adjusted to 9.5 by adding 2 mol of HCl, the mixture was stirred and the two phases were then separated. The organic phase was dried (Na2SO4), filtered and the solvent was evaporated to give an oil which recrystallized from 15 ml of CHaCN

10th

15

20th

25th

30th

35

40

45

50

55

60

65

666 892

28

and gave 0.3 g (32%) of the desired compound; Mp 161 ° C.

Example 2

Method a) Preparation of 4,6-dimethyl-5-heptyloxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1 H-benzimidazole

1.13 g (0.0059 mol) of m-chlorobenzoic acid (91%), in 25 ml of CH2Cl2 and cooled to -10 ° C., became 2.7 g (0.0059 mol) of 4,6-dimethyl with stirring -5-hyptyloxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -l H-benzimidazole,

dissolved in 50 ml of CH2Cl2, the temperature being kept at -5 ° C. Stirring at -5 ° C was continued for 10 minutes. The two phases were separated, after which 0.26 g (0.0066 mol) of NaOH, dissolved in 50 ml of water, was added with vigorous stirring. The two phases were separated, the organic phase was dried (Na2SO4), filtered and the solvent was evaporated. An oil was obtained as a residue which, according to the NMR analysis, contained 30% of unreacted starting material. The oil was chromatographed on a silica column using CH3OH-CH2CI2 (5:95) as eluent, after which the product was recrystallized from CH3CN. This gave 0.85 g (32%) of the desired product in crystalline form; Mp 116 ° C.

Table 2 below shows which of these two methods was used for the preparation of the various sulfoxides. For most of the compounds which were synthesized in accordance with Example 2, no chromatographic separation was carried out.

Example 3

Method b) Preparation of 4,6-dimethyl-5-methoxy-2 - [[(3,4-dimethyl-2-pyridinyl) methyl] thio] -1 H-benzimidazole

1.04 g (0.0050 mol) of 4,6-dimethyl-5-methoxy-2-mercapto-1 H-benzimidazole in 50 ml of methanol were mixed in the order given with 0.2 g (0.0050 mol) of NaOH, dissolved in 2 ml of water, and 0.96 g (0.0050 mol) of 3,4-dimethyl-2-chloromethyl-pyridine hydrochloride were added. The mixture was heated to reflux. Then 0.2 g (0.0050 mol) of NaOH, dissolved in 2 ml of water, was added dropwise and then kept under reflux for a further 3 hours. The mixture was then poured onto 200 ml of ice water. Filtration and recrystallization from CH3CN gave 1.1 g (67%) of the desired product. The NMR data of the final product are given below.

Examples 4 and 5

Method d) Preparation of N1-benzoyl-5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -lH-benzimi-dazole and N'-benzoyl-6 -methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -1 H -benzimidazole

3.0 g (0.009 mol) of 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -1 H-benzimidazole were dissolved in 30 ml of CH3CN and treated with 1 , 9 ml of triethylamine. Then 1.4 g (0.010 mol) of benzoyl chloride was added dropwise with stirring over 15 minutes. After that the

Mixture was stirred at 55 ° C. for 45 minutes. The solvent was evaporated and ether was added to the residue while cooling with ice. The crystalline residue thus obtained was stirred with water, filtered off and dried and gave 1.9 g (48%) of a white, crystalline product mixture with the desired two products in a molar ratio of 75:25 (according to HPLC analysis and NMR analysis) . The NMR data for the end products are given below.

Example 6

Method d) Preparation of N-methoxycarbonyl-5,6-methylenedioxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sul-finyl] -1 H-benzimidazole

0.24 g (0.0026 mol) of chloromethyl formate in 5 ml of CH2Cl2 was added dropwise with stirring to a solution of 0.80 g (0.0022 mol) of 5,6-methylenedioxy-2 - [[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1 H-benzimidazole and triethylamine in 10 ml of CH2C12 were added. The mixture was then stirred at room temperature for 19 hours. The CH2Cl2 solution was washed with water, dried (MgS04) and the solvent evaporated. 0.06 g (6%) of the desired product was obtained in the form of an oil. The NMR data for the final product are given below.

Example 7

Method d) Preparation of NI- (N'-phenylcarbamoyl) -5,6-methylenedioxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridynyl) methyl] sulfinyl] -1 H- benzimidazole

0.20 g (0.00167 mol) of phenyl isocyanate, dissolved in 5 ml of CH2Cl2, was added dropwise with stirring to a solution of 0.50 g (0.00139 mol) of 5,6-methylenedioxy-2 - [[(4-methoxy- 3,5-dimethyl-2-pyridinyl) -methyl] sulfinyl] -1 H-benzimidazole and 0.28 g (0.00278 mol) of triethylamine in 15 ml of CH 2 Cl 2 were added. The mixture was then stirred at room temperature for 50 hours. The CH2C1 solution was washed with water, dried (MgSÜ4) and the solvent was evaporated. 0.03 g (5%) of the desired product was obtained in the form of an oil. The NMR data for the final product are given below.

Example 8

Method e) Preparation of 4,6-dimethyl-5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1 H-benzimidazole

1.0 g (0.0023 mol) of N1-propionyl-4,6-dimethyl-5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl-1H-benzimidazole were heated with stirring and under nitrogen for 1 hour in 50 ml of a 1 molar NaOH solution and the pH was adjusted to 9.5 by adding 2 mol of HCl. Extraction with CH2CI2, separation of the phases, drying of the organic phase, evaporation of the solvent and recrystallization from CH3CN gave 0.30 g (35%) of the desired product; Mp 137 ° C.

Table 2 below gives the data for further examples of the compounds according to the invention.

5

10th

15

20th

25th

30th

35

40

45

50

55

29

Table 2 Compilation of the working examples

666 892

38 s h

40 s h

41 so h ch3

ch,

X'0 "—i ch

^ 0-1

E.g

.X

R15

R1

R2

R3

R4

R5

R6

R7

R8

Method (Ex. No.)

Yield%

Mp (° C) other data

9

S

H

ch3

ch3

CH3

ch3

h ch3

och2ch = ch2

ch3

b

3)

82

164-165

10th

SO

H

ch3

ch3

ch3

ch3

h ch3

och2ch = ch2

ch3

a

2)

73

146-148

11

S

h ch3

ch3

ch3

ch3

h ch3

och3

ch3

b

3)

79

207

12

SO

H.

ch3

ch3

ch3

ch3

h ch3

och3

ch3

a

2).

32

193

13

S

H

ch3

ch3

ch3

h h

ch3

och2ch = ch2

ch3

b

3)

97

165

14

SO

h ch3

• ch3

ch3

h h

ch3

och2ch = ch2

ch3

a

2)

59

147

15

S

h ch3

ch3

ch3

h h

ch3

och3

ch3

b

3)

79

159

16

so h

ch3

ch3

ch3

h h

ch3

och3

ch3

a

1)

83

188

17th

s

H

CH3

ch3

h cn3

h ch3

0CH2CH = CH2

ch3

b

3)

77

NMR

18th

so

H

ch3

ch3

H

ch3

h ch3

0CH2CH = CH2

ch3

a

1)

58

129

19th

s

H

ch3

ch3

H

ch3

H

ch3

och3

ch3

b

3)

79

163

20th

so

H

ch3

ch3

h ch3

H

ch3

och3

ch3

a

D

52

191

21st

s

H

ch3

ch3

H

h h

ch3

och2ch = ch2

ch3

b

3)

37

109

22

so

H

ch3

ch3

H

H

H

ch3

0CH2CH = CH2

ch3

a

1)

58

149

23

s h

h ch3

ch3

h h

ch3

OCH2CH = CH2

ch3

b

3)

99

181

24th

so

H

H

ch3

ch3

H

H

ch3

0CH2CH = CH2

ch3

a

D

71

157

25th

s

H

ch3

H

H

ch3

h ch3

0CH2CH = CH2

ch3

b

3)

62

NMR

26

so

H

ch3

H

H

ch3

H

ch3

0CH2CH = CH2

ch3

a

D

10th

155

27th

s h

ch3

H

h h

H

ch3

0CH2CH = CH2

ch3

b

3)

90

NMR

28

so h

ch3

H

H

h h

ch3

0CH2CH = CH2

ch3

a

D

69

142

29

s h

h ch3

H

H

H

ch3

0CH2CH = CH2

ch3

b

3)

74

NMR

30th

so h

h ch3

H

H

H

ch3

0CH2CH = CH2

ch3

a

D

55

134

31

s h

h och3

H

H

h ch3

0CH2CH = CH2

ch3

b

3)

51

105

32

so h

h och3

h h

H

ch3

0CH2CH = CH2

ch3

a '

D

62

111

33

s

H

h och3

II

H

H

ch3

0CH2cïch ch3

b

3)

66

154

34

so h

H

och3

H

H

H

ch3

0CH2CSCH

ch3

a

D

71

145

35

so

H

h och3

H

H

H

h och3

C2H

5 a

1)

31

147

36

s

H

H

och3

H

H

H

H

- (CHz) 4-

b

3)

61

NMR

37

so

H

h och3

H

H

H

H

- (CH2) 4-

a

2)

34

NMR

h h ch3 ii ch3 h ch,

ch,

ch,

oh

och2ch = ch2 ochzch = ch2

ch,

ch3 ch.

3)

3) D

22

76 35

148

134-136 111

666 892

30th

Ex x r15 r1

R4 R5

8 Method Yield Mp. (° C) R (Ex. No.) y other data i. f * -

42

s h

H

43

so h

H

44

s h

H

45 SO H

47 so H

48 S H

49 SO H

53 S0 H

54 S H

55 S0 H

56 s H 8 SO H 3 S H 1 SO H

57 S H

58 SO H

59 S H

60 SO H

61 S H

62 SO H

63 S H

64 SO H

65 S H

66 SO H

67 S H

68 SO H

69 S H

70 SO H

71 S H

72 SO H

73 S H

74 SO H

75 S H

76 SO H

och2cn och ,, cn

O

c00ch2ch20ch3

cooch cooch

50

s h

h ch2oh

51

so h

rt chgoh

52

s h

h ch2oci

H H H

ch3 ch3 ch3 ch3 ch3 ch3 ch3

ch3

ch3 ch3

tH3

ch3

ch3 ch3 ch3 ch3 ch3

ch,

C2H5 c2h5

ch,

ch20c0 cooch,

cooch,

oh

ch3 Cl

Cl och,

oh

och

och2ch2och3 och2ch2och3 0ch2ch20ch3 0ch2ch20ch3 coch,

c0ch3

coch3 coch3 coc2h5

c0c2hb

L2H5 C2H5

C2Hb

4H5 cn cn och3 och3 Cl Cl h h h

ch3

och3

ch3

b

3!

29

66

h h h

ch3

och3

ch3

at

39

94

h h h

ch3

och3

ch3

b

3)

75

NMR

h h h

ch3

och3

ch3

a

2)

60

155

ch3 h h

ch3

och3

ch3

a

ch3 h

H

ch3

och3

ch3

c

ch3 h h

ch3

och3

ch3

a

ch3 h h

ch3

och3

ch3

b

3)

86

192

ch3 h h

ch3

och3

ch3

a

1)

10th

169

ch3 h h

ch3

och3

ch3

c

ch3 h h

ch3

och3

ch3

a

ch3 h h

ch3

och2ch = ch2

ch3

b

3)

75

168

ch3 h h

ch3

och2ch = ch2

ch3

a

D

52

139

ch3 h h

ch3

och3

ch3

b

3)

70

NMR

ch3 h h

ch3

och3

ch3

{!

l \

56 35

137 137

ch3 h h

ch3

ch3

h b

3)

67

NMR

ch3 h h

ch3

ch3

H

a

1)

32

161

ch3 h h

ch3

och3

ch3

b

3)

90

NMR

ch3 h h

ch3

och3

ch3

a

1)

68

144

ch3 h h

h ch3

ch3

b

3)

95

NMR

ch3 h h

h ch3

ch3

a

1)

58

131

ch3 h h

ch3

och3

ch3

b

3).

90

192-4

ch3 h h

ch3

och3

ch3

a

2)

25th

164-5

ch3 h h

ch3

H.

ch3

b

3)

99

184-6

ch3 h h

ch3

h ch3

a

2)

91

148-50

ch3 h h

ch3

och3

ch3

b

3)

68

149

ch3 h h

ch3

och3

ch3

a

2)

48

NMR

ch3 h h

ch3

och3

ch3

b

3)

91

182

ch3 h h

ch3

och3

ch3

a

2)

67

175-7

ch3 h h

ch3

och3

h b

3)

95

NMR

ch3 h h

ch3

och3

h a

2)

73

142-3

c2h5 h h

ch3

och3

ch3

b '

• 3)

82

150

c2h5 h h

ch3

och3

ch3

a

2)

81

180

ch3 ch3

h ch3

och3

ch3

b '

3)

82

143

ch3 ch3

h ch3

och3

ch3

a

2)

43

163

Cl h h

ch3

och3

ch3

b

3)

90

204

Cl h h

ch3

och3

ch3

a

31 666892

E.g.

x r15

r1

r2

r3

r4

r5

r6

r7

r8

Method (example number)

yield

%

Mp (° C) other data

77

so h

h ch3

ch3

h h

H

0ch3

C2H5

a

1)

43

156

CH3 ~ 7 ~ \

78

s h

h cov_>

h h

h ch3

och3

ch3

b

3)

90

nmr

c "3> - \

79

so h

H

C0IW

h h

h ch3

och3

ch3

a

1)

61

nmr

80

s h

H

-0ch20-

h h

ch3

och3

ch3

b

3)

91

168

81

so h

H

-0ch20-

h h

ch3

och3

ch3

a

' 1)

67

165

82

s h

-ch = ch

-ch = ch-

h h

h ch3

och3

ch3

b.

3)

73

nmr

83

so h

-ch = ch

I.

O

X

II

o X

h h

h ch3

och3

ch3

a

1)

60

184

84

s h

H

-ch = ch-ch = ch-

h h

ch3

och3

ch3

b

3)

78

191

85

so h

H

-ch = ch-ch = ch-

h h

ch3

och3

ch3

a

• 1)

34

175

86

s h

-ch2ch

2ch2CIV

h h

h ch3

och3

ch3

b

3)

58

nmr

87

so h

-ch2ch

2ch2ch2-

H

H

h ch3

° ch3

ch3

a '

1)

27th

175

88

s h

H

-och2o-

•

h co2ch3

ch3

0ch3

ch3

d •

6

so h

H

-och2o-

h co2ch3

ch3

0ch3

ch3

d

6)

6

nmr

7 SO H H -OCHzO- H CONH - ^^ CH-j OCH3 CH3 d 7) 5 NMR

90 S H H 0CH2CH2CH20 - ^^ H H H CH3 OCHj CH3 b 3) 25 NMR

91 SO H H 0CH2CH2CH20 - <^) H H H CH3 0CH3 CHj a 2) 78 51

92

s h

ch3

o (ch2) 6ch3

ch3

h h

ch3

och3

ch3

b

3)

64

NMR

2nd

so h

ch3

o (ch2) 6ch3

ch3

h h

ch3

och3

ch3

a

2)

32

116

93

s h

H

C2H5

h h

h ch3

0ch2ch = ch2

ch3

b

3)

45

NMR

94

so h

H

C2H5

h h

h ch3

och2ch = ch2

ch3

a

1)

49

124-6

95

S

H

H

och3

h h

h ch3

0ch2ch2ch (ch3) 2

ch3

b

■ 3}

95

NMR

96

so

H

h och3

H

h h

ch3

0ch2ch2ch (ch3) 2

ch3

a

1)

33

111

97

s h

-ch =

= ch-ch = c-ch2ch2-

h h

ch3

och3

ch3

b.

3)

96

190

98

so h

-ch =

1

= ch-ch = c-ch2ch2-

h h

ch3

och3

ch3

a

2)

93

109

4- S H H OCH, H H C0- (O> CH, OCH, CH, d 4) |

> ^ (t 48 NMR

5 S H H H OCH3 H CO-aJ)) CHg OCHj CH3 d 5)

99 S H H CH (CH3) 2 H H H CH3 0CH2CH = CH2 CH3 b 3) 99 70

101 S H H C (CH3) 3 H H H CH3 OCH2CH = CH2 CH3 b 3) 52 88-89

102 SO H H C (CH3) 3 H H H CH3 0CH2CH = CH2 CH3 a 2) 12 NMR

103 s H H CH2CH2OCH3 H H H CH3 0CH3 CH3 b 3) 84 NMR

104 SO H H CH2CH2OCH3 H H H CH3 OCH3 CH3 a 1) 38 118

105 S H H P. H H CH3 0CH3 CH3 b 3) 58 216

106 S0 H H CJ H H CH3 0CH3 CH3 a 2) 32 158

666 892

32

, 15 "1

r3 r4

r6 r7

E.g.

Method Yield Mp. (° C) Ex. No.) other data

107

so h

H

0ch3

h h

co2ch3

ch3

och3

108

so h

h h

och3

h co2ch3

ch3

och3

109

s h

h sch3

h h

ii ch3

oh

110

S

h h

ch (ch3) 2

h h

h ch3

ochp ch,

d

4 '+

3rd

ch3

d

ch3

b

3)

CH3

b

3)

5)

117 S H

118 SO H

119 S H

120 SO H

121 S H

122 SO H

123 S H

H

H 0 H OCH-CH

H CO H CO H

° ^ 2>

- <2> - ©

X °>

H OCH ^ CHg

124

so h

H

125

s h

h s0ch3

126

so h

h so3

127

so h

h no2

128

s h

H

Br

129

so h

H

Br

130

s h

h och3

131

so h

h och3

132

so h

h ch3

134

so h

h ch3

135

s h

h ch3

136

so h

h ch3

137

s h

H

138

so h

H

139

s h

-ch

= ch-ch = i

140

so h

-ch

= ch-ch = i

H H

H H

H H

H H

H H

H H

H II

H H

ch3 h ch3 ii

-ch2ch2ch2- h

-CH2CM2CH2- H

h h h h

H H H II H

CH,

CH,

CH,

CH,

CH,

CH,

CH-

CH,

OCH,

OCH,

OCH,

OCH,

OCH,

OCH,

OCH,

OCH,

h h

h ch3

och3

h h

h ch3

och3

h h

h ch3

och3

h h

h ch3

0ch2ch = ch.

h h

h ch3

0ch2ch = ch,

h h

H

-CH = i ch-0-

h h

H

-ch-

ch-0-

ch3

H

? oc (ch3

'3 ch3

0ch3

ch3

H

? n (ch3)

2 ch3

och3

CH,

CH,

™ i-Q

cll3 och3

CH,

CH,

ch,

CH,

CH,

CH,

CH,

3)

2)

3)

2)

3)

2)

3)

ch,

CH,

ch,

3)

98 80 80 55 82 24 88

74

r

<nmr 147-148-

^ NMR

111

so h

h ch (ch3)

h h

h ch3

ochO

ch3

a

2)

89

^ NMR

112

s h

h ch2ch2c0ch3

h h

h ch3

och2ch = ch2

ch3

b

3)

40

] h NMR

113

so h

h ch2ch2c0ch3 '

h ii h

ch3

och2ch = ch2

ch3

a

2)

28

123-4

114

115

s s

h h h h c ^ 0

0CH3

h h h h h h ch3

-ch =

och3 • ch-ch = ch-

ch3

h b b

3) 3)

21 67

162 105

116

50

h h

0CH3

h h

H

-ch =

: ch-ch = ch-

h a

1)

66

100

122 118 ^ NMR 145 d] H NMR

'h wfe

158

ch3

a

2)

52

104

ch3

b

• 3)

57

] h NMR

ch3

a

1)

47

^ NMR

ch3

a

. 1)

14

NMR

ch3

b

3)

64

171

ch3

a

2)

58

143

h b

3)

77

NMR

h a -

2)

19th

NMR

ch3

d

6)

22

168

ch3

d

6)

21st

^ NMR

160

h ch3

och3

ch3

a

1)

40

171

h ch3 "

'och3

ch3

b

3)

38

NMR

h ch3

och3

ch3

a

1)

26

60

33

666 892

R ^ R1

E.g.

r4 r5

Method Example No.)

Yield mp (° C)

% other data

141 s

142 so

143 so

144 s

145 so

146 s

147 so

148 s

149 so

150 s

151 so

152 s

153 so h h h h h h ch

0 II

coch3

ch,

h ch, ch,

h ch, ch,

h ch, ch,

h ch3 ch3 h ch, ch,

h ch, ch,

h ch, ch,

h ch,

h ch,

cn cn h h

161 so h h

163 so h h

164 so h h

165 so h h

166 so h h ch2ch2cooc2h5

oh

oh

oh

oh

oh

-och2o-och2o ch3 ch3 ch3 ch3 ch3 ch3 ch3 h h

ch3 ch3

h h h h h h h h h h h h h h h h h h h h ch,

h ii h

II

h h

h h

h h h h h h ch3 h h h h

h h

h h

h ch3 ch3

h ch3 ch3

h h ch3

ch3

ch3

ch3

ch ch h

II

ch,

ch ch ch ch

H3J3

ch3 ch3

och3

ch3

ch3

ch3

ch3

h h ch3

ch,

-ch2ch2o - CHzch2ch20-h h ch3 ch3

c2h5 h h

ch3 ch3 ch3 ch3

h h

3) 2)

2)

3)

2)

3)

2)

3)

2)

3) 2)

3)

83 76

49 39

65 78 64 70 14 96

66

71

193-95 173

154 1

h nmr

'h nmr

143

180

239-42

171

210

hnft

3rd

oc2h5

ch3

b

3)

94

151

3rd

ocjjhjj ch3

1

2)

29

150

ch3

C2H5

b

3)

48

1H NMS

ch3

C2H5

a

2)

44

105

'3

0ch2ch20ch3

ch3

b

3)

94

1H NMR

'3

0ch2ch20ch3

ch3

a

2)

18th

181

'3

"i-Ç>

ch3

b

3)

67

100

'3

ok

ch3

a

2)

57

125

f3

0CH3

ch3

b

3)

15

^ nmr ch3

0CH3

ch3

d

6)

50

155

H NMR

-och2ch2 - och2ch2ch2-

50

Identification data for compounds of the invention NMR data of the compounds listed in Table 2 (90 MHz)

Example NMR data: S (CDCb) ppm

No.

17 2.3 (s, 3H), 2.35 (d, 6H), 2.5 (s, 3H), 2.55 (s, 3H), 4.4 (s, 2H), 4.25-4.4 (d, 2H), 5.2-5.6 (m , 2H), 5.9-6.4 (m, lH), 6.9 (s, lH), 8.35 (s, lH).

27 2.2 (s, 3H), 2.3 (s, 3H), 2.6 (s, 3H), 4.35-4.45 (d, 2H), 4.45 (s, 2H), 5.2-5.6 (m, 2H), 5.85-6.35 (m, lH), 6.9-7.55 (m, 3H), 8.3 (s, lH).

29 2.2 (s, 3H), 2.25 (s, 3H), 2.4 (s, 3H), 4.2-4.35 (d, 2H), 4.4 (s, 2H), 5.5-5.6 (m, 2H), 5.85-6.3 (m, lH), 6.9-7.l (d, lH), 7.3-7.55 (t, 2H), 8.3 (s, lH).

55

Example NMR data: S (CDCb) ppm no.

60

65

36 1.8 (m, 4H), 2.75 (m, 4H), 3.8 (s, 3H), 4.25 (s, 2H), 6.85 (m, lH), 7.05 (s, 2H), 7.4 (d, lH), 8.3 (s, lH).

37 1.7 (m, 4H), 2.3-2.7 (m, 4H), 3.85 (s, 3H), 4.6 (d, 2H), 6.8 (s, lH), 7.05 (s, 2H), 7.6 (m, lH ), 8.3 (s, lH).

44 1.2-2.0 (m, 10H), 2.25 (s, 3H), 2.3 (s, 3H), 2.6 (m, lH), 3.75 (s, 3H), 4.45 (s, 2H), 7.1 (q, lH ), 7.5 (m, 2H), 8.35 (s, lH).

3 2.3 (s, 6H), 2.35 (s, 3H), 2.5 (s, 3H), 3.75 (s, 3H), 4.4 (s, 2H),

7.05-7.2 (d, lH), 7.25 (s, lH), 8.3-8.45 (d, lH).

57 2.2 (s, 3H), 2.25 (s, 3H), 2.3 (s, 3H), 2.5 (s, 3H), 3.45 (s, 3H), 3.75 (s, 3H), 3.85 (m, 4H), 4.3 (s, 2H), 7.2 (br.s "1H), 8.3 (s, lH).

666 892

34

Example NMR data: S (CDCh) ppm no.

59 2.3 (s, 6H), 2.4 (s, 3H), 2.55 (s, 3H), 3.5 (s, 3H), 3.9 (m, 4H), 4.3 (s, 2H), 7.2 (s, lH), 7.3 (s, lH), 8.4 (s, lH), 9.3 (br.s., 1H).

66 1.2 (t, 3H), 2.15 (s, 3H), 2.2 (s, 3H), 2.3 (s, 3H), 2.4 (s, 3H), 2.8 (q, 2H), 3.65 (s, 3H), 4.8 (s, 2H), 7.3 (s, lH),

8.25 (s, lH).

69 l. L (t, 3H), 2.2 (s, 3H), 2.4 (s, 3H), 2.55 (s, 3H),

2.75 (q, 2H), 3.85 (s, 3H), 4.35 (s, 2H), 6.75 (d, lH), 7.25 (s, lH), 8.4 (d, lH).

78 1.2 (d, 3H), 1.6 (m, 6H), 2.25 (s, 3H), 2.3 (s, 3H), 3.0 (m, lH), 3.75 (s, 3H), 4.15 (m, lH), 4.45 (s, 2H), 4.55 (m, lH), 7.3 (q, lH), 7.6 (m, 2H), 8.3 (s, lH).

79 1.25 (d, 3H), 1.65 (m, 6H), 2.15 (s, 3H), 2.2 (s, 3H), 3.1 (m, 1H), 3.65 (s, 3H), 4.1 (m, 1H) , 4.6 (m, 1H), 4.8 (s, 2H), 7.4 (q, lH), 7.7 (d, lH), 7.8 (s, lH), 8.3 (s, lH).

82 2.2 (s, 3H), 2.3 (s, 3H), 3.7 (s, 3H), 4.75 (s, 2H), 7.3-8.5 (m, 8H).

86 1.85 (m, 4H), 2.2 (s, 3H), 2.25 (s, 3H), 2.7-3.1 (m, 4H), 3.75 (s, 3H), 4.35 (s, 2H), 6.9 (d, lH ), 7.3 (d, lH), 8.25 (s, lH).

6 2.2 (s, 3H), 2.35 (s, 3H), 3.8 (s, 3H), 4.15 (s, 3H), 4.75 (s, 2H), 6.1 (s, 2H), 7.3 (s, lH), 7.5 (s, lH), 8.15 (s, lH).

7 2.15 (s, 3H), 2.2 (s, 3H), 3.7 (s, 3H), 4.7 (s, 2H), 6.05 (s, 2H), 7.0-7.6 (m, 7H), 8.15 (s, lH ), 8.3 (s, lH).

90 2.25 (s, 3H), 2.1-2.4 (m, 2H), 2.3 (s, 3H), 3.75 (s, 3H),

4.2 (t, 4H), 4.4 (s, 2H), 6.75-7.2 (m, 5H), 7.2-7.6 (m, 3H), 8.35 (s, lH).

92 0.7-2.05 (m, 13H), 2.25 (s, 3H), 2.3 (s, 3H), 2.35 (s, 3H), 2.5 (s, 3H), 3.65-3.9 (m, 2H), 3.75 (s , 3H), 4.35 (s, 2H), 7.2 (s, lH), 8.3 (s, lH).

93 1.25 (t, 3H), 2.25 (s, 3H), 2.3 (s, 3H), 2.8 (q, 2H),

4.4 (d, 2H), 4.45 (s, 2H), 5.2-5.65 (m, 2H), 5.85-6.3 (m, lH), 7.0-7.65 (m, 2H), 7.5 (s, lH), 8.35 ( s, lH).

95 0.9 (s, 3H), 1.0 (s, 3H), 1.5-1.95 (m, 2H),

2.15-2.45 (m, lH), 2.25 (s, 3H), 2.3 (s, 3H), 3.7-4.0 (t, 2H), 3.85 (s, 3H), 4.45 (s, 2H), 2.8-7.0 ( m, lH), 7.15 (d, lH), 7.45-7.55 (d, lH), 8.3 (s, lH).

4 + 5 2.25 (s, 3H), 2.40 (s, 3H), 3.6 and 3.85 (2s, total 3H), 3.80 (s, 3H), 4.8 and 4.85 (2s, total 2H), 6.35-7.95 (m, 8H), 8.35 (s, 1H).

103 2.3 (s, 3H), 2.35 (s, 3H), 3.0 (t, 2H), 3.35 (s, 3H),

3.65 (t, 2H), 3.8 (s, 3H), 4.4 (s, 2H), 6.8-7.6 (m, 4H), 8.25 (s, lH).

107 + 1082.2 (s, 3H), 2.35 (s, 3H), 3.75 (s, 3H), 3.9 and 3.95 (2s, total 3H), 4.15 (s, 3H), 4.75 (s, 2H), 7.07-7.95 (m, 3H), 8.15 (s, lH).

102 1.32 (s, 9H), 2.08 (s, 3H), 2.15 (s, 3H), 4.09 (d, 2H), 4.74 (s, 2H), 5.10-5.45 (m, 2H), 5.73-6.25 (M , lH), 7.28-7.73 (m, 3H), 8.27 (s, lH).

139 2.22 (s, 3H), 2.29 (s, 3H), 3.75 (s, 3H), 4.40 (s, 2H),

7.38-7.58 (m, lH), 7.87-8.02 (m, 2H), 8.29-8.47 (m, lH), 8.70-9.00 (m, 2H).

110 1.25 (d, 6H), 1.6-2.15 (m, 4H), 2.25 (s, 3H), 2.3 (s, 3H), 3.0 (m, lH), 3.7-4.05 (m, 4H), 4.25 (m , lH), 4.5 (s, 2H), 7.15 (q, lH), 7.5 (s, lH), 7.55 (d, lH), 8.3 (s, lH).

111 1.3 (d, 6H), 1.55-2.15 (m, 4H), 2.2 (s, 3H), 2.25 (s, 3H), 3.05 (m, lH), 3.65 (d, 2H), 3.9 (m, 2H) ), 4.2 (m, lH), 4.8 (s, 2H), 7.3 (d, lH), 7.4-7.8 (m, 2H), 8.3 (s, lH).

119 2.3fs, 3Hj, 2.35 (s, 3H), 3.15 (t, 2H), 3.7 (s, 3H),

4.25Ct, 2Hj, 4.4 (s, 2H), 6.9 (q, lH), 7.15 (d, lH), ".3 - i.KmfiH), 8.35 (s, lH).

125 2 3's, 3H ;, 2.35 (s, 3H), 2.8 (s, 3H), 3.8 (s, 3H), 4.5 (s, 2H), ~ -5 «dJ Hj, 7.75 (d, lH), 8.05 (s, lH), 8.4 (s, lH).

Example NMR data: S (CDCb) ppm no.

126 2.2 (s, 6H), 2.8 (s, 3H), 3.7 (s, 3H), 4.85 (s, 2H), 7.6 (q, lH), 7.85 (d, lH), 8.15 (s, lH), 8.25 (s, lH).

127 2.25 (d, 6H), 3.75 (s, 3H), 4.9 (d, 2H), 7.8 (d, lH), 8.3 (s, lH), 8.3 (q, lH), 8.65 (d, lH).

134 2.2 (d, 6H), 2.35 (d, 6H), 3.1 (s, 6H), 3.7 (s, 3H), 4.95

(s, 2H), 7.2 (s, lH), 7.6 (s, lH), 8.3 (s, lH). 112 2.1 (s, 3H), 2.25 (s, 3H), 2.3 (s, 3H), 2.65-3.2 (m, 4H),

4.4 (d.2H), 4.42 (s, 2H), 5.2-5.6 (m, 2H), 5.9-6.4 (m, lH), 7.1 (dd, lH), 7.4 (d, lH), 7.5 (d, lH), 8.35 (s, lH).

121 2.25 (s, 3H), 2.35 (s, 3H), 3.8 (s, 3H), 4.45 (s, 2H), 7.45-8.0 (m, 7H), 8.15 (s, lH), 8.4 (s, lH ).

122 2.2 (s, 6H), 3.7 (s, 3H), 4.8 (d, 2H), 7.5-8.05 (m, 7H), 8.2 (s, lH), 8.25 (s, lH).

144 2.25 (s, 3H), 2.35 (s, 6H), 2.38 (s, 3H), 2.55 (s, 3H), 4.4 (s, 2H), 7.15 (d, lH), 7.3 (s, lH), 8.4 (d, lH).

145 2.15 (s, 3H), 2.23 (s, 3H), 2.27 (s, 3H), 2.4 (s, 3H), 2.47 (s, 3H), 4.8 (s, 2H), 7.1 (d, lH), 7.3 (s, lH), 8.37 (d, lH).

151 2.2 (s, 3H), 2.23 (s, 3H), 2.35 (s, 3H), 2.4 (s, 3H),

2.47 (s, 3H), 4.8 (d, 2H), 7.0 (s, lH), 7.1 (d, lH), 8.37 (d, lH).

130 3.85 (s, 3H), 4.65 (s, 2H), 6.8-7.8 (m, 7H), 8.55 (d, lH).

131 3.85 (s, 3H), 4.95 (d, 2H), 6.65-7.60 (m, 7H), 8.45 (d, lH). 160 1.15 (t, 3H), 2.20 (s, 3H), 2.27 (s, 3H), 2.49-2.74 (m, 2H),

2.89-3.13 (m, 2H), 3.72 (s, 3H), 4.09 (q, 2H), 4.37 (s, 2H), 6.98 and 7.08 (dd, lH), 7.30-7.55 (m, 2H), 8.28 ( s, lH). 154 l.l-2.1 (m, 13H), 2.3 (s, 3H), 2.5-2.8 (m, 3H), 4.4 (s, 2H),

7.1-7.65 (m, 4H), 8.5 (s, lH).

156 ll-2.0 (m, l 1H), 2.25 (s, 3H), 2.3 (s, 3H), 3.45 (s, 3H), 3.7 (t, 2H), 4.0 (t, 2H), 4.4 (s, 2H), 7.05-7.65 (m, 3H), 8.35 (s, lH).

164 2.13 (m, 2H), 2.88 (t, 2H), 3.82 (s, 3H), 4.26 (t, 2H), (270 4.69 (s, 2H), 6.7-6.85 (m, 2H), 7.04 (d , lH), 7.39 (d, lH), MHz) 8.1 (d, lH).

Preparation of the intermediate stages Example 11

Method A) Preparation of 4,5,7-trimethyl-2-mercapto-1H-benzimidazole

10.2 g (0.057 mol) of 2-nitro-3,4,6-trimethylaniline were dissolved in 900 ml of 95% ethanol and then hydrogenated in the presence of a Pd / C catalyst until the theoretical amount of hydrogen was consumed (1 hour ). The entire mixture was transferred to another flask and 12.8 g (0.080 mol) of potassium ethyl xanthate, dissolved in 12.5 ml of water, were added. The mixture was heated to reflux overnight, then 20 ml of a 2 molar NaOH solution was added and the volatiles were evaporated. The residue was dissolved in 300 ml of methanol and the catalyst was filtered off. A portion of the solvent (200 ml) was evaporated. Then 100 ml of water were added and the mixture was acidified with 10 ml of acetic acid dissolved in 20 ml of water. The crystalline precipitate formed was filtered off, washed with water and dried under reduced pressure. 7.2 g (66%) of the desired product were obtained; NMR: 5 (CDCh), 2.0 (s, 3H), 2.05 (s, 3H), 2.1 (s, 3H), 3.3 (br.s, 1H), 6.5 (s , lH).

Example 12

Method B) Preparation of 4,6,7-trimethyl-5-methoxy-2-mercapto-1 H-benzimidazole

A solution of 1.8 g (0.010 mol) of 4-methoxy-3,5,6-trimethyl-l, 2-phenylenediamine and 2.1 g (0.021 mol) of triethylamine in 15 ml of CHCh was added dropwise to a with stirring Solution of 0.60 g (0.0052 mol) thiophosgene in 5 ml CHCh

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

35

666 892

admitted. The mixture was then stirred at room temperature for one hour. Then 15 ml of water and 0.5 g of triethylamine were added and the mixture was stirred for 1 hour. The precipitate was filtered off, washed with water and air dried. 0.96 g (43%) of the desired product was obtained; NMR: 8 (CDCb) 2.5 (s, 3H), 2.65 (s, 6H), 3.65 (s, 3H), 12.0 (br.s., lH).

Example 13

Method C) Preparation of 4-allyloxy-3,5-dimethyl-2-pyridinyl-methanol

4.0 g (0.021 mol) of 4-allyloxy-2,3,5-trimethyl-pyridine-N-oxide were added dropwise to 8.0 ml (0.062 mol) of acetic anhydride, which had been preheated to 80 ° C., with stirring , whereby a final temperature of 120 ° C was reached. The mixture was then kept at 80 ° C. for one hour by heating. Then 15.0 ml of methanol were added and the mixture was kept at 80 ° C. for 15 minutes. The volatiles were evaporated under reduced pressure. Then 20 ml of 10% HCl was added and the mixture was heated to 90 ° C. for 1 hour and then cooled to room temperature. An excess of 2 molar NaOH solution was added and the mixture was extracted with CH2Cl2. The organic phase was separated and dried. After evaporation of the volatiles, 3.0 g (75%) of the desired product was obtained in the form of an oil; NMR: ô (CDCh) 2, l (s, 3H), 2.25 (s, 3H), 4.4 (m, 2H), 4.65 (s, 2H), 4.75 (s, lH) , 5.2-5.65 (m, 2H), 5.9-6.45 (m, lH), 8.3 (s, lH).

Example 14

10 Method D) Preparation of 4-allyloxy-3,5-dimethyl-2-pyridinyl-methylchloride hydrochloride

4.8 ml of thionyl chloride, dissolved in 12 ml of CH2CI2, were added dropwise with stirring to a solution of 8.0 g (0.041 mol) of 4-allyloxy-3,5-dimethyl-2-pyridinylmethanol in 80 ml of 15 CH2CI2, the temperature being reduced to a minimum was kept below 6 ° C. The mixture was then stirred at room temperature for 5 minutes, reaching a final temperature of 15 ° C. Then 2 ml of isopropanol were added and the solution briefly warmed to 35 ° C. The solvent was evaporated off and the crystalline residue was recrystallized from ethanol / ether. 3.0 g (29%) of the desired product were obtained; Mp 115 ° C.

25th

Table 3a intermediate stages. List of working examples:

? la

No.

to rla r2a r3a r4a

R5a

Jfethode Ex. No.)

Out-

fp- (° c) other data

15

sh ch3

ch3

ch3

ch3

h a

II)

19th

nmr

16

sh ch3

ch3

ch3

h h

a

II)

66

nmr ii sh ch3

ch3

h ch3

h a

II)

66

nmr

17th

sh h

h h

h a

II)

71

nmr

18th

sh ch3

0CH3

ch3

■ h h

a

II)

78

nmr

19th

sh ch3

0ch2ch20ch3

ch3

h h

a

II)

85

nmr

110

sh ch3

c2h5

ch3

h h

a

H)

89

nmr in sh h

0ch2ch2ch2cm ^^>

h h

h a

II)

14

167

112

sh ch3

0 (ch2) 5ch3

ch3

h h

a

II)

73

nmr

12

sh ch3

° ch3

ch3

ch3

H

B

12)

43

nmr

113

sh

-ch =

= ch-ch = ch-ch? ch? -

h h

a

II)

23

NMR

X Ì

'Method A: 1,2-phenylenediamine was reacted with C2HgOCS2K. Method B: 1,2-phenylenediamine is reacted with CSC ^.

666 892

36

Table 3b intermediate stages. List of work

Play R7a:

, 6a

N ^ XHg-Z23

No

.z2a r53

r7a

R8a

Salt / base

Method ** 'Example No.)

Yield (%)

Mp. (° C) other data

13

oh ch3

och2ch = ch2

ch3

Base c

13)

75

■ nmr

14

cl ch3

och2ch = ch2

ch3

hcl d

14)

29

115 °

114

oh ch3

och2c = ch ch3

Base c

13)

88

70 °

115

Cl ch3

och2c = ch ch3

HCl d

14)

76

135 °

116

oh h

- (ch2) 4-

Base c

13)

35

nmr

117

Cl h

- (ch2) 4-

hcl d

14)

72

nmr

118

oh ch3

0ch2ch2ch (ch3) 2

ch3

Base c

13)

51

NMR

119

cl ch3

0ch2ch2ch (ch3) 2

ch3

HCl

D

14)

95

120

Oh ch3

oc "zO

ch3

Base c

13)

30th

MMR

121

Cl ch3

OCHyQ

ch3

HCl

0

14)

82

133

122

OH

ch3

oc2h5 u

CH ',

base

C.

13)

70

s.d. 120-26 ° C 0.4 fr, m

123

Cl ch3

oc2h5

ch3

HCl d

14)

89

157

124

OH

-CH =

ch-0-

H

base

C.

13)

18th

] h nmr

125

Cl

-CH =

CH-0-

H

HCl

0

14)

95

195

xx)

Method C

: Rearrangement of

Pyridine-N-oxide with (CH3

C0) 20.

Method D: chlorination with SOCI,

NMR data of the compounds in Table 3a and Table 3b

Example No.

NMR data: ô (ppm)

Example NMR data: S (ppm) No.

15 S (DMSO-dö) 2.05 (s, 6H), 2.2 (s, 6H).

16 S (CDCb) 2.05 (s, 3H), 2.15 (s, 3H), 2.2 (s, 3H), 3.2 (s, 2H), 5s 6.7 (s, lH).

11 8 (CDCb) 2.0 (s, 3H), 2.05 (s, 3H), 2.1 (s, 3H),

3.3 (br.s., lH), 6.5 (s, lH).

17 ô (DMSO-d6) l. L-2.05 (m, 10H), 2.4 (m, lH), 6.85-7.05 (m, 3H).

18 8 (DMSO-dò) 1.95 (s, 3H), 2.0 (s, 3H), 3.35 (s, 3H), 6.55 (s, lH).

19 8 (CDCb) 2.1 (s, 3H), 2.15 (s, 3H), 3.2 (s, 3H), 3.35-3.8 (m, 4H), 6.6 (s, lH).

110 8 (CDCh + DMSO-ds) 1.05 (t, 3H), 2.3 (s, 3H),

2.35 (s, 3H), 2.6 (q, 2H), 6.85 (s, lH).

112 S (CDCb) 0.5-1.7 (m, 13H), 2.0 (s, 3H), 2.1 (s, 3H), 3.15 (s, 2H), 3.35-3.6 (m, 2H), 6.6 (s, lH) .

60

65

12 6 (CDCh) 2.5 (s, 3H), 2.65 (s, 6H), 3.65 (s, 3H), 12.0 (br.s., lH).

113 8 (CDCb) 3.35 (s, 2H), 3.4 (s, 2H), 7.15-8.05 (m, 4H), 12.65 (br.s., lH), 13.3 (br.s., lH).

13 8 (CDCh) 2.1 (s, 3H), 2.25 (s, 3H), 4.4 (m, 2H), 4.65 (s, 2H), 4.75 (s, lH), 5.2-5.65 (M, 2H), 5.9 -6.45 (m, lH), 8.3 (s, lH).

116 ô (CDCb) 1.6-1.9 (m, 4H), 2.5-2.8 (m, 4H), 4.7 (s, 2H), 7.3 (s, lH), 8.2 (s, lH).

117

118 8 (CDCb) 1.0 (s, 3H), 1.05 (s, 3H), 1.5-2.05 (m, 3H), 2.15 (s, 3H), 2.3 (s, 3H), 3.75-4.0 (t, 2H) , 4.15-4.5 (br.s., lH), 4.65 (s, 2H), 8.3 (s, lH).

120 8 (CDCb) 1.7-2.2 (m, 4H), 2.15 (s, 3H), 2.25 (s, 3H), 3.75-4.05 (m, 4H), 4.15-4.4 (m, lH), 4.6 (s, 2H), 8.25 (s, 1H).

124 8 (CDCb) 8.55 (d, 1H), 7.8 (d, 1H), 7.5 (d, lH), 7.0 (d, 1H), 5.1 (s, 2H)

37

666 892

Pharmaceutical preparations which contain a compound according to the invention as active component are described in the following examples.

Example 167 - Syrup

A syrup containing 1% w / v was made from the following ingredients;

4,6-Dimethyl-5-ethyl-2 - [[(4-methoxy-3,5-

dimethyl-2-pyridinyl) methyl] thio] -lH-

benzimidazole • HCl 1.00 g

Sugar, powdered 30.00 g

Saccharin 0.60 g

Glycerin 5.00 g

Flavoring 0.05 g

Ethanol (96%) 5.00 g

Distilled water q.s. ad 100 ml

Sugar and saccharin were dissolved in 60 g of warm water. After cooling, the acid addition salt was dissolved in the sugar solution and glycerin and a solution of a flavoring agent in ethanol were added. The mixture was made up to a final volume of 100 ml with water.

The above-mentioned active substance can be replaced by other pharmaceutically acceptable acid addition salts.

Example 168 - Enteric coated tablets

An enteric coated tablet containing 20 mg of an active component was prepared from the following ingredients;

I. 5,6-methylenedioxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridine) methyl] sulfmyl] -

1 H-benzimidazole 200 g

Lactose 700 g

Methyl cellulose 6 g

Polyvinyl pyrrolidone, cross-linked, 50 g

Magnesium stearate 15 g

Sodium carbonate 6 g

Dest.water q.s.

II. Cellulose acetate phthalate 200 g

Cetyl alcohol 15 g

Isopropanol 2000 g

Methylene chloride 2000 g

I. 5,6-methylenedioxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -l H-benzimidazole in powder form was mixed with lactose and mixed with an aqueous solution of Granulated methyl cellulose and sodium carbonate. The moist mass was passed through a sieve and the granules obtained were dried in an oven. After drying, the granules were mixed with polyvinyl pyrrolidone and magnesium stearate. The dry mixture was compressed into tablet cores (10,000 tablets), each containing 20 mg of active substance, in a tablet machine using 6 mm diameter punches.

II. A solution of cellulose acetate phthalate and cetyial alcohol in isopropanol / methylene chloride was sprayed onto tablets I, using a Manesty coating device (“Accela Cota”). The weight of the finished tablet was 110 mg.

Example 169 - Solution for intravenous administration

A parenteral preparation suitable for intravenous administration and containing 4 mg of active ingredient per ml was prepared from the following ingredients;

4,6-Dimethyl-5-ethyl-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -1 H-benzimidazole 4 g polyethylene glycol 400 (for injections) 400 g disodium hydrogen phosphate q.s. Sterile water q.s. ad 1000 ml

4,6-Dimethyl-5-ethyl-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -1 H-benzimidazole was dissolved in polyethylene glycol 400 and with 550 ml of water transferred. The pH of the solution was adjusted to 7.4 by adding an aqueous solution of disodium hydrogenphosphate and the volume of the solution made up to 1000 ml. The solution was filtered through a filter with a pore diameter of 0.22 μm and immediately filled into sterile ampoules with a capacity of 10 ml, whereupon the ampoules were sealed.

Biological studies

I. In vitro inhibitory effect on gastric acid secretion in isolated rabbit gastric glands

Test method gastric gland preparation

Isolated gastric glands from rabbits were, as in Berglindh et al., Acta physiol. scand. 1976.96. Pp. 150-159. This method involves vascular perfusion of the rabbit stomach over the gastric arteries, scraping and crushing the separated gastric mucosa with scissors and enzymatic degradation with collagenase (0.1%, Type I, Sigma Chemicals, St. Louis, MO.USA) at 37 ° C during 60 to 90 minutes. The glandular tissue was then harvested and filtered through a nylon cloth to remove coarse fragments. Thereafter, the glandular tissue at 37 ° C in a medium containing 132.4 mM NaCl, 5.4 mM KCl, 5.0 mM NaH2PO <t, 1.0 mM NaH2P04.1.2 mM MgSO4.1.0 mM CaCh , 10 mM glucose and 1 mg / ml rabbit albumin and showed a pH of 7.4.

Measurement of acid secretion

Acid secretion in the isolated glandular tissue preparation was recorded by measuring the uptake of I4C-labeled aminopyrine in the glands as described by Berglindh et al., Acta physiol. scand. 1976.97. Pp. 401-414. The accumulation of aminopyrine in the glands indicates gastric acid secretion in the glands. The standard medium contained 10-6 M 14C-aminopyrine (Amersham, Great Britain). After the incubation, the glands were centrifuged, the supernatant solution removed and the glands dried, weighed and dissolved in Soluen 350 (Packard, IU. USA). Samples of the supernatant solution and glands were counted separately in a scintillation counter. The accumulation of 14C-labeled aminopyrine in the cells was calculated as described by Berglindh et al., Acta physiol. scand. 1976, 97. p. 403, described in detail.

Test protocol

The glands were incubated for 60 minutes in the presence of 5 x IO-5 M histamine and the test compound to be examined. The free base of the test compound was dissolved in methanol. The final concentration of methanol was 1% in the incubation medium and had no influence on the ratio of the aminopyrine accumulation. A complete dose response was obtained for each test compound5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

666 892

38

curve generated by examining the doses to be examined twice in a concentration range from IO-7 to IO-4 M. The logarithm of the concentration (in M) of the test compound, which gave a 50% inhibition of aminopyrin accumulation in the glands (ICso), is shown in Table 4 below.

II. Inhibitory effects in vivo on gastric acid secretion in conscious dogs

Test method

Dogs with chronic gastric fistula were used. In these dogs, a cannula was surgically inserted into the stomach and a duodenal fistula was also used to directly insert the test compounds into the duodenum. After a recovery period of 4 weeks after the surgical intervention, the tests were carried out once a week in each dog. Food and water were withdrawn 18 hours before each test. Gastric acid secretion was controlled by continuous infusion of histamine into individual

Doses (100 to 300 nmol / kg, h) triggered and resulted in submaximal gastric acid secretion. At least two hours after the onset of stimulation, when gastric acid secretion had reached a constant level, 5 the test compounds were in the form of the free bases, suspended in 5% strength “Methocel” (90 HG, 15,000, Dow Chem. Corp.), in doses of 1 to 8 p, mol / kg introduced into the duodenum. The gastric juice, which flowed freely through the gastric cannula, was collected in successive 30-minute samples for 3 hours. The samples were titrated to pH 7.0 with 0.1 molar NaOH using an automatic radiometer titrator and the acid formed calculated.

The percent inhibition of acid secretion was calculated by comparing the acid delivery in each dog during the test to the acid delivery in control trials in which only the vehicle was administered. The maximum inhibitory effect for each compound is shown in Table 5 below.

20th

Table 4 Biological effects in isolated rabbit maggot glands

R7

A <H_x ^ /

r1 £

^ r2

V

i5

r4

r1

r2

r3

r4

r3

r6

r7

r8

-l ° ë ic50

ch3

ch3

ch3

ch3

h ch3

och3

ch3

6.5

ch3

ch3

ch3

h h

ch3

och3

ch3

6.5

h och3

h h

h h

- (ch2) a-

5.0

H

0ch2cn h

h h

ch3

och3

ch3

4.4

h ch20h ch3

h h

ch3

0ch3

ch3

M

h ch2ch20ch3

h h

h ch3

och3

ch3

5/7

ch3

0ch3

ch3

h h

ch3

och3

ch3

6.5

ch3

och3

ch3

h h

ch3

c «3

H

6 7

t ch3

och2ch2och3

ch3

h h

ch3

0ch3

ch3

5) 9

ch3

och2ch2och3

ch3

h h

h ch3

ch3

5.4

ch3

c0ch3

ch3

h h

ch3

0ch3

ch3

6.2

ch3

c0ch3

ch3

h h

ch3

h ch3

5.8

ch3

c0c2h5

ch3

h h

ch3

och3

ch3

6.0

ch3

c2h5

ch3

h h

ch3

0ch3

ch3

6.5

ch3

c2 »5

ch3

h h

ch3

och3

H

5.9

c2h5

cn c2h5

h h

ch3

och3

ch3

5.0

ch3

0ch3

ch3

ch3

h ch3

och3

ch3

6.2

h ch3> —v conJ>

h h

h ch3

0ch3

ch3

5.0

No.

12 16 37 43 51 104 8 l 58 bO 62 64 66 6b

70 72 74 r-i

, 15th

SO H

SO H

SO H

SO H

SO H

SO H

SO H

SO H

SO H

SO H

SO H

SO H

SO H

SO H

SO H

SO H

SO H

SO H

No.

81

83

107

108

10th

14

18th

20th

22

24th

26

28

30th

32

34

35

41

45

55

87

91

2nd

94

96

98

102

104

106

111

39

666 892

X R15 R1

"log IC

£ 3 L

so h so h

-och2o-

-ch = ch-ch = ch-

h h ch3 0ch3 ch3 h h ch3 0ch3 ch3

ß

6rl

5.5 5.3

so h so h so h so h so h so h so h so h so h so h so h so h so h so h so h so h so h so h so h so h so u so h so h sc h so h so h so h so h so hhh och

ch3 ch3

ch3 ch3

ch3 ch3

ch3 ch3

ch3 ch3

h ch_

ch3 h ch3 h h h h h ch3 och3

och3

och-

ch3 h

»" O

h coochn

-ch2ch2ch2ch2-

h 0CH2CH2CH20- <5) H

ch3 0 (ch2) 6ch3

C2H5 OCH "

-ch = ch-ch = cch2ch2 "

c (ch3) 3

chgchgoch,

tl H

h h h h ch (ch3) 2 ch2ch2coch3

Hg> '

SO H H OCH2CH; p (o)

h h

co2ch3

och3

h c02ch3

ch3

ch3

h i cu3

h h i h

ch3

h i h

ch3

h h

h h

ch3

h h

h ch3

h h

h h

h h

h h

h h

h h

h h

h h

ch3

h h

h h

h ch3

h h

h h

H

) H

H

H

ch3

H

H

H

H

H

U

H

H

H

H

h h

h h

ì

h h

/

h h

h h

h h

h h

h h

h h

H

h chch

5.8

6.1

6.1

ch3

och2ch = ch2

ch3

5.9

ch3

och3

ch3

6.0

ch3

och2ch = ch2

ch3

6.0

ch3

och2ch = ch2

ch3

6.0

ch3

0ch2ch = ch2

ch3

5.9

ch3

och2ch = ch2

ch3

5.9

ch3

och2ch = ch2

ch3

5.9

ch3

och2ch = ch2

ch3

5.6

ch3

OCH2C = CH

ch3

5.0

h och3

c2h5

5.6

ch3

och2ch = ch2

ch3

5.9

ch3

och3

ch3

6.1

ch3

och2ch = ch2

ch3

5.3

ch3

och3

ch3

6.3

ch3

och3

ch3

5.8

ch3

och3

ch3

5.9

ch3

och2ch = ch2

ch3

6.6

ch3

och2ch2ch (ch3) 2 ch3

6.1

ch3

och3

ch3

5.6 '

ch3

och2ch = ch2

ch3

5.9

ch3

och3

ch3

5.7

ch3

och3

ch3

6.0

ch3

och ^ qJ

ch3

6.2

ch3

0ch2ch = ch2

ch3

5.8

ch3

och3

ch3

6.4

ch3

och3

ch3

6.3

No.

124

129

142

143

145

147

149

151

153

77

159

7 * "

H

H

40

x

R13

R1

R2

R3

R4

R5

Rb

R7

R8

-log I.C50

so h

H

- <5>

h h

h ch3

och3

ch3

7.0

so h

H

Br h

h h

ch3

och2ch = ch2

ch3

6.0

so

H

H

-och2o-

H

H

ch3

ch3

ch3

6.0

so h

H

J)

c och3

ch3

h h

h och3

C2H5

6.1

so h

ch3

ch3

ch3

h h

ch3

ch3 •

H

6.2

so h

ch3

ch3

ch3

h h

h ch3

ch3

6.4

so h

ch3

ch3

ch3

h h

ch3

h ch3

6.2

so h

ch3

ch3

h ch3

h ch3

ch3

H

6.3

so h

ch3

cn ch3

h h

ch3

oc2H5

ch3

5.2

so h

h ch3

ch3

h h

h och3

c2h5

6.0

SO H

CF.

h ch3 och2

■ O

CH.

6.3

Table 5 Biological effects in conscious dogs

R1 R2

R3 R4 R5 R6 R7

H SCH-

-CH = CH-CH = CH- H H CH3 OCHg CH3

H H H CH3 0CH3 CH3

(1.0.) Dose (^ imol / kg)% inhibition

85 60

Comment on the test results

It can be seen from Tables 4 and 5 that the compounds examined exert a strong inhibitory effect on gastric acid secretion, both in vitro and in vivo.

Claims (15)

666 892 1 1 5 \ Oi (V) wherein R15, X, R1, R2, R3, R4, R6, R7 and R8 have the meaning given in claim 1, by reaction with a 3o acylating agent which is derived from that of potassium isocyanate, (R14C0) 20 and R14COX ', in which X1 is a removable group, selected group is formed, acylated; and then, if desired, converting the compound of formula I obtained, wherein X is -S-, into a physiologically-acceptable salt. (1) R6 and R7 or R7 and R8 together with the adjacent carbon atoms in the pyridine ring form a ring, the part formed by R6 and R7 or R7 and R8 -CH = CH-CH = CH, -0- (CH2) p - CH2 (CH2) p - O-CH = CH-, -NH-CH = CH- or -N-CH = CH- corresponds to, where p is 2, 3 or 4 and the O and N atoms are always bound to the 4-position of the pyridine ring, mean, and the physiologically acceptable salts of compounds of formula I, wherein X is S; with the requirements (a) that only one of the symbols R6, R7 and Rs represents hydrogen; (b) that when X is SO, R5 H and R6, R7 and R8 are only hydrogen, methyl, methoxy, ethoxy, methoxyethoxy or ethoxyethoxy and at the same time more than one of the symbols R1, R2, R3 and R4 are hydrogen, of R1, R2, R3 and R4 at least one is not selected from alkyl, halogen, alkoxycarbonyl, alkoxy or alkanoyl; (c) that if XS, R5, H, alkanoyl or alkoxycarbonyl and R6, R7 and R8 only mean hydrogen, methyl, ethyl, methoxy, ethoxy, methoxyethoxy or ethoxyethoxy and at the same time more than one of the symbols R1, R2, R3 and R4 Is hydrogen, at least one of R1, R2, R3 and R4 is not selected from alkyl, halogen, alkoxycarbonyl, alkoxy, alkanoyl, trifluoromethyl or -NO2; (d) that when X SO, one of the symbols R6, R7 and R8 is hydrogen and the other two of the symbols R6, R7 and R8 are alkyl and at the same time more than one of the symbols R1, R2, R3 and R4 is hydrogen, from those Radicals R1, R2, R3 and R4, which are not hydrogen, at least one not from alkyl, halogen, cyano, 0 0 -C- (alkoxy), (alkyl) -OC- (alkyl) -, Alkoxy, hydroxyalkyl, -CF3 or (alkyl) -c- is selected; and (e) that when R3, R4, R5 and R15 are hydrogen and simultaneously R6 and R8 are H or CH3 and R7 are -OCH3, R1 is not -CF3 when R2 is hydrogen and R2 is not -CF3 when R1 is hydrogen . (1) alkylthio of 1 to 6 carbon atoms; (m) -NO2; (m) alkylsulfinyl of 1 to 6 carbon atoms; or (o) adjacent groups R1, R2, R3 and R4 together with the adjacent carbon atoms in the benzimidazole ring are a 5-, 6- or 7-membered monocyclic ring or a 9-, 10- or 1-membered bicyclic ring, these rings being saturated or unsaturated and zero can contain up to 3 heteroatoms from the group -N- and -O- and are optionally substituted 1 to 4 times, the substituents being those of alkyl having 1 to 3 carbon atoms and alkylene radicals having 4 to 5 carbon atoms, which are spiro compounds result, existing group is selected or two or four of these substituents together form one or two oxo groups, 0 V (-C-), where if R \ R2, R3 and R4 together with the adjacent carbon atoms in the benzimidazole ring form two rings which can be condensed with one another, then in the formulas given Ru and R12, which are the same or different, (a) aryl; (b) alkoxy of 1 to 4 carbon atoms; (c) alkoxyalkoxy having 1 to 3 carbon atoms in each. Alkoxy part; (d) arylalkoxy having 1 to 2 carbon atoms in the alkoxy part; (e) aryloxy; (f) dialkylamino having 1 to 3 carbon atoms in the alkyl moieties; or (g) pyrrolidino or piperidino, optionally substituted with alkyl having 1 to 3 carbon atoms; R13 (a) alkyl of 1 to 4 carbon atoms; or (b) alkylene of 2 to 3 carbon atoms; represent where R9 (a) alkoxy of 1 to 5 carbon atoms; or 30 (b) dialkylamino having 1 to 3 carbon atoms in the alkyl moieties; m zero or 1; r zero or 1; Y (a) -0-; 35 (b) -NH-; (c) -NR10-; R10 (a) H; (b) alkyl of 1 to 3 carbon atoms; (c) arylalkyl having 1 to 2 carbon atoms in the alkyl part; 40 or (d) aryl; and R5 (a) H; or O 2. Compounds according to claim 1, characterized in that at least three of the radicals R1, R2, R3 and R4 are different from hydrogen or form at least one ring. 2nd PATENT CLAIMS 1. Compounds of Formula I 3. Compounds according to claim 1, characterized in that two of the radicals R6, R7 and R8 form a ring structure and the third of the radicals R6, R7 and R8 is H or alkyl. 3rd 666 892 (f) alkoxyalkoxy having 1 to 2 carbon atoms in each alkoxy group; (g) dialkylaminoalkoxy having 1 to 2 carbon atoms in the alkyl substituents attached to the amino nitrogen and 1 to 4 carbon atoms in the alkoxy group; (h) oxacycloalkyl having one oxygen atom and 3 to 7 carbon atoms; (i) oxacycloalkoxy with two oxygen atoms and 4 to 7 carbon atoms; (j) oxacycloalkylalkyl having one oxygen atom and 4 to 7 carbon atoms; (k) oxacycloalkylalkoxy having two oxygen atoms and 4 to 6 carbon atoms; or 4th (II) with a compound of formula III 4. A compound according to claim 1, characterized in that R5 and RIS are H; at least three of the radicals R1, R2, R3 and R4 are different from hydrogen; R6 and R8 each represent H or -CH3 and R7 -CH3, -OCH3 or -OCH2CH = CH2. 5 where pa is 2, 3 or 4 and the O atom is always bound to the R7a position; and Z2a (a) SH; (b) halogen; or (c) OH; io, provided that only one of the symbols R6a and R8a represents hydrogen, as a means for carrying out the method according to claim 11. 5 666 892 15. Compounds of formula VIII -, 1a (VIII), wherein Rla, R2a, R3a and R4a are the same or different and have one of the following meanings: (Ah; (b) alkyl of 1 to 6 carbon atoms, including cycloalkyl; (c) alkoxyalkyl having 1 to 3 carbon atoms in the alkoxy part and 1 to 6 carbon atoms in the alkyl part; (d) aryloxyalkyl having 1 to 6 carbon atoms in the alkyl part; (e) arylalkyl of 1 to 6 carbon atoms in the alkyl part; (f) aryl; (g) alkoxy of 1 to 6 carbon atoms; (h) alkoxyalkoxy having 1 to 3 carbon atoms in the outer part and 1 to 6 carbon atoms in the part closest to the aromatic ring; (i) aryloxyalkoxy having 1 to 6 carbon atoms in the alkoxy part; (j) arylalkoxy having 1 to 6 carbon atoms in the alkoxy part; and (k) aryloxy; R5a (a) H; (b) alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy part; (c) arylalkoxycarbonyl having 1 to 2 carbon atoms in the alkoxy part; (d) dialkylaminocarbonyl having 1 to 4 carbon atoms in each alkyl group; or (e) arylaminocarbonyl; and Zla (a) SH; (b) mean Cl or Br, with the proviso that only one of the symbols Rla, R2a, R3a and R4a is hydrogen, as a means for carrying out the method according to claim 11. 16. Compounds of formula IX , 2a (IX), wherein R6a and R8a (a) H or (b) alkyl of 1 to 5 carbon atoms; and R7a (a) alkenyloxy of 2 to 5 carbon atoms; (b) alkynyloxy of 2 to 5 carbon atoms; (c) oxacycloalkyl having one oxygen atom and 3 to 7 carbon atoms; (d) oxacycloalkoxy having 2 oxygen atoms and 4 to 7 carbon atoms; (e) oxacycloalkylalkyl having one oxygen atom and 4 to 7 carbon atoms; (f) oxacycloalkylalkoxy with two oxygen atoms and 4 to 6 carbon atoms; or (g) R6a and R7a or R7a and R8a together with the adjacent carbon atoms in the pyridine ring form a ring, in which the part formed by R6a and R7a or R7a and R8a is one of the groups -CH = CH-CH = CH-, -0- (CH2) pa-, -CH2- (CH2) pa- and -O-CH = CH-, 5 5. Pharmaceutical preparation which contains a compound as claimed in one of claims 1 to 4 as active component. 6. Veterinary preparation which contains a compound as claimed in one of claims 1 to 4 as active component. 6 (I) where X -S- or * -S- Z -0- or -C-; R15 H, CH3 or C2H5; R1, R2, R3 and R4, which are the same or different, (Ah; (b) halogen; (c) -CN; (d) -CHO; (e) -CF3; O , 7th wherein R1, R2, R3, R ", R5, R6, R7, R8, R15 have the meanings given in claim 1 and X is -S-, characterized in that a compound of formula IV VIV) R 7. Use of a compound according to any one of claims 1 to 4 or a therapeutically acceptable salt thereof for the manufacture of agents for inhibiting gastric acid secretion in humans and mammals. 8. Use of a compound according to any one of claims 1 to 4 or a therapeutically acceptable salt thereof for the manufacture of cell protective agents for the gastrointestinal tract in humans and mammals. 9. Use of a compound according to any one of claims 1 to 4 or a therapeutically acceptable salt thereof for the preparation of agents for the treatment of inflammatory diseases of the gastrointestinal tract in humans and mammals. 9 9 -C-R (Y) m 0 II (C). - R 10th (III), wherein R1, R2, R3, R4, R5, R6, R7, R8 and R1S have the meanings given above and one of the symbols Z1 and Z2 -SH and the other represent a cleavable group; and then, if desired, converting the compound of formula I obtained, in which X is -S-, into a physiologically acceptable salt. 10th 15 20th 25th 30th 35 40 45 50 55 60 65 666 892 10. Process for the preparation of a compound of formula I. R X CH f-i n wherein R1, R2, R3, R4, R5, R6, R7, R8, R15 have the meanings given in claim 1 and X has the meaning given below, characterized in that for the preparation of a compound of formula I, wherein X means oxidizes a compound of formula I, wherein X is -S-. 10th (h) -CH (OR13) 2; (i) - (Z) n-A-D; (j) aryl; (k) aryloxy; 11. Process for the preparation of a compound of formula I. CH R R wherein R1, R2, R3, R4, R5, R6, R7, R8, R15 have the meanings given in claim 1 and X is -S-, characterized in that for the preparation of a compound of the formula I in which X is -S- means a compound of formula II "11 -C-R; (f) (G) 0 of -O-C-R 20th 25th n zero or 1; A (a) alkylene of 1 to 6 carbon atoms; (b) cycloalkylene of 3 to 6 carbon atoms; (c) alkenylene of 2 to 6 carbon atoms; (d) cycloalkenylene of 3 to 6 carbon atoms; or (e) alkynylene of 2 to 6 carbon atoms; and D (a) -CN; 12. A process for the preparation of a compound of formula I. wherein R1, R2, R3, R4, R6, R7, R8, R15 and X have the meanings given in claim 1 and R5 corresponds to the group R14CO, characterized in that for the preparation of a compound of formula I, wherein R5 is group 15 RI4CO corresponds, where R14 is as defined in claim 1, a compound of formula V. 12 (b) (c) 13. Process for the preparation of a compound of formula I. bsivr r1 (VI), z3 ra wherein X, R15, R1, R2, R3, R4, R6, R7 and R8 have the meanings given in claim 1 65 and Z3 represents an N-protecting group, hydrolyzes and then the compound of formula I obtained if X -S- means, if desired, converted into a physiologically acceptable salt. 14. Process for the preparation of a compound of formula I -, 40 45 (I) wherein R1, R2, R3, R4, R6, R7, R8, RIä and X have the meanings given in claim 1 and R5 means hydrogen, characterized in that for the preparation of a compound of formula I, wherein R5 is hydrogen , a compound of formula VI wherein R15, R5, R6, R7 and R8 have the meanings given above and Y1, Y2, Y3 and Y4 either correspond to R1, R2, R3 and R4 or the groups (Z) nA-COOH, -COOH or (Z) nA- Represent OH, where Z, n and A are as defined in claim 1, with a corresponding alcohol R9OH, R, 0OH or a carboxylic acid R10COOH, where R9 and R10 are as defined in claim 1, to give a compound of the formula I, which contains a radical R1, R2, R3 and / or R4 which corresponds to one of the ester groups (Z) "- A-COOR9, COOR10 or (Z) nA-OCOR10; and then, if desired, converting the compound of formula I obtained, in which X is -S-, into a physiologically acceptable salt. 14 (b) -C-R represent where R14 (a) alkyl of 1 to 6 carbon atoms; (b) arylalkyl having 1 to 2 carbon atoms in the alkyl part; (c) aryl; so (d) alkoxy of 1 to 4 carbon atoms; (e) arylalkoxy having 1 to 2 carbon atoms in the alkyl part; (f) aryloxy; (g) amino; 55 (h) mono- or dialkylamino having 1 to 4 carbon atoms in the alkyl part or in the alkyl parts; (i) arylalkylamino having 1 to 2 carbon atoms in the alkyl part; and (j) arylamino; Represent 60; R6 and R8, which are the same or different, (a) H; or (b) alkyl of 1 to 5 carbon atoms; and R7 (a) H; b5 (b) alkyl of 1 to 8 carbon atoms; (c) alkoxy of 1 to 8 carbon atoms; (d) alkenyloxy of 2 to 5 carbon atoms; (e) alkynyloxy of 2 to 5 carbon atoms; 15